Poland Sequence

Unilateral congenital malformation of the anterior chest wall, defined by agenesis or hypoplasia of the pectoralis major, with variable involvement of the breast, nipple–areola complex, rib cage and ipsilateral upper limb; mostly sporadic, with no established gene, and included in the family of sequences caused by disruption of subclavian artery blood flow.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding description and eponym

In 1841, Poland published in Guy's Hospital Reports, under the title «Deficiency of the pectoral muscles», the description of an individual lacking the pectoralis minor and the sternal portion of the pectoralis major, whose hand on the same side had fingers joined by skin [1, 14]. The description was anatomical and isolated, and for more than a century the association between the pectoral defect and ipsilateral syndactyly was reported under various names, such as the «syndactyly with absence of the pectoralis major» of Brown and McDowell in 1940 [1]. The eponym became established after Clarkson published in 1962, in the same journal, the article «Poland's syndactyly» [14, 24]. The attribution of the name was debated in 1977 by Ravitch and McDowell, who questioned whether the 1841 report justified the eponym; the term persisted and is the one used by OMIM (Online Mendelian Inheritance in Man) and Orphanet [1, 2].

1.2. From syndrome to sequence: the vascular hypothesis

In 1972, David studied ten patients and found a high proportion of potentially harmful prenatal influences: five were adopted and the mothers of the other five had attempted to terminate the pregnancy in early gestation [1, 25]. In 1976, Bouvet, Maroteaux and Briard-Guillemot measured reduced blood flow in the affected limb and proposed a primary developmental defect of the proximal subclavian artery [14, 26]. In 1986, Bouwes Bavinck and Weaver extended this proposal and grouped Poland anomaly, Klippel-Feil anomaly, Möbius sequence, isolated absence of the pectoralis major with breast hypoplasia, isolated terminal transverse limb defects and Sprengel deformity into a common category, the subclavian artery supply disruption sequence (SASDS), in which the site and duration of the interruption of flow, around the 6th week of gestation, would determine the pattern of defects [27]. The term «sequence» derives from this hypothesis: a pattern of anomalies resulting from a single primary event, and not a set of defects with a common genetic cause [14]. Orphanet, OMIM and the 2020 Italian consensus keep the designation «syndrome» as the main name and record «sequence» and «anomaly» as synonyms [1, 2, 10].

1.3. Broadening and limits of the phenotype

In 1989, Fraser and colleagues described two second cousins, one with the complete phenotype and the other with absence of the pectoralis major only, and proposed including the isolated pectoral defect in the spectrum of the sequence [1]. Al-Qattan later regarded isolated pectoral hypoplasia or aplasia as the mildest form of the syndrome, whereas the original definition presupposed thoracic and upper-limb anomalies [28]. Conversely, Riccardi described in 1978 unilateral gluteal hypoplasia with brachysyndactyly of the foot as the lower-limb equivalent of Poland anomaly, an interpretation supported by a family with gluteal hypoplasia in three women and pectoral hypoplasia in the proband (Parano, 1995) and by a 1997 case attributed to disruption of the territory of the external iliac artery [1]. The existence of a bilateral form is controversial: the case published as the first bilateral Poland anomaly (Karnak, 1998) was reinterpreted by Maroteaux and Le Merrer as a thoracic dysplasia, and Shipkov and Anastassov argued in 2003 that the syndrome is by definition unilateral; Baban and colleagues described in 2009 a girl with asymmetric bilateral pectoral defects and reviewed the cases with bilateral features [1, 10, 29].

1.4. Associations with other sequences and genetic milestones

Coexistence with Möbius sequence was described by Gadoth in 1979, and Parker and colleagues gathered in 1981 at least twelve documented cases, which they regarded as a distinct malformation syndrome; the designation «Poland–Möbius» is attributed to Herrmann, and the first description to Jorgenson in 1971 [5, 11]. Reports followed of coexistence with Adams-Oliver syndrome in two families (Der Kaloustian, 1991), with the oculo-auriculo-vertebral spectrum (Cobben, 1992) and with Klippel-Feil anomaly (Erol, 2004) [1, 30]. The genetic basis was sought from families with recurrence: the Genoa series published in 2012 quantified familial recurrence in 190 families examined [9], the Istituto Giannina Gaslini group described in 2014 a de novo deletion at 11q12.3 in concordant monozygotic twin girls [31] and in 2016 analysed CNV in 120 patients, without finding recurrent alterations [7]. In 2015, the discovery of de novo variants in PLXND1 and REV3L in Möbius syndrome provided candidate genes for the combined phenotype [8]. As of October 2026 no gene responsible for the isolated form has been identified, and OMIM records the association with PLXND1 only as pending confirmation [1]. The most recent clinical systematisation is the 2020 Italian Delphi consensus, promoted by AISP within the European Reference Network on rare bone diseases (ERN-BOND) [10].

1.5. Definition and scope

This article adopts the definition of the 2020 consensus: agenesis or hypoplasia of the pectoralis major, with constant involvement of the sternocostal head, is the mandatory criterion; hypoplasia or aplasia of the ipsilateral mammary gland and nipple and malformations of the ipsilateral upper limb, limited to the central rays or more severe in them, are additional criteria [10]. The Orphanet definition adds hypoplasia of the pectoral subcutaneous tissue and absence of pectoral and axillary hair [2]. A systematic review of 627 patients found ten different definitions in use, and only 29% of published patients had the classical form with pectoral defect and ipsilateral symbrachydactyly, which explains part of the heterogeneity of figures in the literature [32]. The article covers the isolated form and the forms associated with other malformations, including Poland–Möbius sequence and craniofrontonasal dysplasia–Poland anomaly syndrome (Webster-Deming syndrome), of which only two cases or families are known and with no report since 1994 [4]. This is not a class of syndromes with numbered subtypes. Klippel-Feil syndrome and Holt-Oram syndrome enter the differential diagnosis of upper-limb defects.

2. Molecular Genetics and Pathophysiology

2.1. State of aetiological knowledge

The aetiology and pathogenesis of Poland syndrome (PS) are unknown [3, 10, 14]. Most cases are sporadic, and the marked asymmetry of the phenotype is used as an argument against a simple Mendelian cause; the existence of familial cases and the possibility of mosaicism leave open a genetic contribution, and the 2020 consensus admits a multifactorial polygenic model [10]. The Oxford Desk Reference summarises the current state as a probably multifactorial basis with vascular disruption in early development [33]. OMIM classifies entry 173800 with the prefix «%», used for phenotypes with unknown molecular basis, and lists no gene with an established phenotype–gene relationship [1]. In practice, the diagnosis remains clinical, and the aetiological hypotheses described below guide investigation and counselling without providing a confirmatory test [10].

2.2. Vascular hypothesis: the subclavian artery supply disruption sequence

The most widely accepted hypothesis attributes PS to an early insufficiency of flow in the subclavian artery, placed by the consensus around the 45th day of embryonic life and, by other authors, in the 6th or 7th week of gestation [10, 27, 28]. Bavinck and Weaver located the interruption in the subclavian artery proximal to the origin of the internal thoracic artery and distal to the origin of the vertebral artery, which would explain hypoplasia of the anterior chest wall and of the distal limb with preservation of the posterior cerebral circulation [14]. In the SASDS formulation, interruption of flow in the subclavian, the vertebral or their branches, at specific locations, would produce predictable patterns: involvement of the vertebral territory or of the primitive trigeminal arteries would explain Möbius sequence and Klippel-Feil anomaly, and the coexistence of these entities in the same individual would be the expression of a more extensive disruption [14, 27, 34]. Recent reviews add that the more proximal the occlusion, the more severe the phenotype would be [35]. Arguments in favour include the demonstration of reduced flow in the affected limb by Bouvet and colleagues, the description of a reduction of more than 50% in subclavian calibre and flow velocity in patients with PS, and the overlap with defects of known disruptive cause [14, 26, 28]. The mechanism that would interrupt flow is unknown; Bavinck and Weaver discussed compression of the vessel by oedema [36].

The chronology of limb development makes this window plausible. The upper limb buds appear around day 27 after fertilisation, the hand plate between days 34 and 38, the digits begin to separate between days 38 and 40 and are fully separated by days 52–53 [33]. Syndactyly results from failure of digit separation during this period or from an external disruptive event during embryonic development [37]. The symbrachydactyly typical of PS, with aplasia or hypoplasia of the middle phalanges of the central digits, corresponds to a transverse defect that relatively spares the thumb [3].

In 2026, a case of right pectoral deficiency with transverse deficiency of the upper limb at carpal level, without residual ectodermal elements, was presented as difficult to explain by a vascular interruption at a single point and as an argument in favour of a dynamic embryonic capillary plexus model [38]. The report does not demonstrate the mechanism and illustrates the main limitation of the vascular hypothesis: it is compatible with most phenotypes but has not been verified experimentally in human embryos.

2.3. Environmental factors

Maternal smoking during pregnancy was associated with an approximately twofold risk of PS in the Hungarian population-based registry of congenital anomalies and in the Spanish hospital-based case–control study (ECEMC, Estudio Colaborativo Español de Malformaciones Congénitas), with similar results in both programmes; the authors stressed that the sample was small and that the finding required confirmation [39]. Exposure to cocaine and misoprostol and in vitro fertilisation have also been mentioned in isolated cases, particularly in the Poland–Möbius phenotype [5, 28]. Misoprostol, chorionic villus sampling (CVS) and phenytoin are recognised teratogens through vascular disruption of already formed limbs, and CVS before 10 weeks is associated with the oromandibular-limb hypogenesis spectrum [33, 40]. These exposures are absent in the vast majority of patients and do not allow an individual cause to be attributed.

2.4. Familial recurrence and inheritance models

The Genoa multidisciplinary series examined 240 patients and, in 190, also the parents [9]. Eight families (4.2%) had true recurrence of the pectoral defect; sixteen (8.4%) were «Poland-like» families, in which the index case had PS and at least one relative had normal pectoral muscles but upper-limb or thoracic anomalies typical of the syndrome; 166 (87.4%) were sporadic [9]. In families with true recurrence, males (87.5%) and the left side (62.5%) predominated, upper-limb anomalies were less frequent (37.5%) and transmission was maternal in six of the eight families, differences without statistical significance given the sample size [9]. The authors reviewed 31 published families and concluded that the familial form is not rare and that there are no clinical or molecular tools to identify the risk of recurrence [9].

Familial reports describe parent-to-child transmission (Trier, 1965; Fuhrmann, 1971, with father-to-son transmission), affected second cousins (David, 1982; Fraser, 1989), mother and daughter (Cobben, 1989) and three generations of males with unilateral absence of the pectoralis major, serratus anterior and latissimus dorsi (David and Winter, 1985) [1]; Shalev and Hall published in 2003 another family with transmission across generations [33, 41]. Maternal transmission and male predominance in families led to consideration of X-linked genes, a hypothesis weakened by male-to-male transmission [14]. In some families, one member has PS and another a unilateral terminal transverse limb defect without pectoral defect, which suggests an inherited predisposition to a common disruptive event [1]. In two families, different members had PS and Adams-Oliver syndrome, and the authors considered that a gene predisposing to interruption of subclavian flow might be transmitted in an autosomal dominant manner [30]. Czeizel and colleagues interpreted a Hungarian family, with affected father and son and severe hypoplasia of the thumb, as a possible dominant pectoral-radial defect distinct from PS [1]. The models considered are thus autosomal dominant inheritance with incomplete penetrance and variable expressivity, autosomal recessive inheritance and, hypothetically, X-linked inheritance, none of which has been demonstrated molecularly [7, 10]. Orphanet records autosomal dominant, autosomal recessive, multigenic or multifactorial and «not applicable» inheritance, which reflects this heterogeneity and not an established mode of inheritance [2].

Intrafamilial expressivity is highly variable: in several sibships, the proband has complete PS and a sibling or parent only some features, without hypoplasia of the pectoralis major [14]. Therefore, clinical examination of parents and siblings in search of minimal forms is part of the assessment [10].

2.5. Copy number variations

The largest CNV study included 120 sporadic Italian patients (76 male and 44 female; pectoral agenesis in 51 and hypoplasia in 69; right side in 71), assessed at the Istituto Giannina Gaslini between 2008 and 2015 by karyotype and array comparative genomic hybridisation (array-CGH) with a resolution of 13 to 22 kb, with 600 individuals as internal controls [7]. A total of 14 rare heterozygous CNV were found in 14 patients, seven duplications and seven deletions of 0.04 to 4.71 Mb, none recurrent; parental origin could be studied in 11, of which three were de novo and eight inherited from a clinically unaffected parent (seven maternal and one paternal) [7]. One patient had a 5p15.2 duplication resulting from a balanced maternal translocation t(5;11)(p15.1;q21) and another a 47,XXY karyotype [7].

Coordinates in hg19 in the original article; R, right; L, left [7].

Functional analysis of the 119 genes included in the CNV showed enrichment in the cadherin pathway (FYN, CDH6, CDH9, FRK, CDH12), the Wnt pathway, coagulation, apoptosis, microtubule movement, chondrocyte differentiation and the myosin thick filament [7]. Among the candidates, LAMA4 drew attention because the deficient mouse has haemorrhages and capillary defects, which would be compatible with the vascular hypothesis, and TRIO because the deficient mouse has a myogenesis defect; REV3L is associated with Möbius syndrome, but the patient with the 6q21-q22.1 deletion had no signs of Möbius [7]. The authors concluded that CNV are a rare cause of PS and that, being mostly inherited from unaffected parents, they probably behave as susceptibility or modifier alleles rather than as a direct cause [7]. The 16p13.11 region is also altered in controls and is associated with neurodevelopmental disorders, which reinforces this caution [7]. In the Genoa familial series, array-CGH in 13 families showed three maternally inherited CNV (1p31.1 deletion, Xp11.22 duplication and 16q23.1 duplication); the mother carrying the 16q23.1 duplication had moderate asymmetry of the breast and areola with sonographically normal pectoral muscles [9].

2.6. 11q12.3 deletion in monozygotic twins

In Chilean monozygotic twin girls concordant for right-sided PS, a heterozygous interstitial deletion of 126 kb, arr[hg19] 11q12.3(63,216,306-63,342,369)x1, was identified, absent in the parents and the two siblings and located on the paternally derived chromosome [31]. The deletion includes HRASLS5, LGALS12, RARRES3, HRASLS2 and the end of PLA2G16, genes of the type II HREV107 family, tumour suppressors that modulate the RAS pathway; sequencing of these genes on the remaining allele showed no deleterious variants, and the CNV was absent from the Database of Genomic Variants and from 200 internal controls [31]. In an independent group of 30 sporadic patients, the only candidate variant, a missense change in HRASLS5 (p.Arg28Gln, described by the authors only by the hg19 genomic coordinate and without a reference transcript), had been inherited from the healthy father, so the authors regarded it at most as a predisposing factor [31]. The proposed hypothesis, as yet undemonstrated, is that haploinsufficiency of RARRES3 increases HRAS activity and inhibits myogenesis [31]. Concordance in monozygotic twins is an argument in favour of genetic control, but PS has also been described in only one of two identical twins, and the differences in severity between the two sisters were attributed to epigenetic, somatic, environmental or microvascular factors [31]. The same region was later found deleted de novo in one patient of the series of 120 (patient 9 in the previous table) [7].

2.7. Poland–Möbius sequence: PLXND1 and REV3L

In Möbius syndrome, a 2015 multicentre study identified de novo variants in PLXND1 and REV3L in some patients; mice mutant for both genes had convergent defects in the facial branchiomotor nucleus [8]. PLXND1, at 3q22.1, encodes plexin D1, a semaphorin receptor highly expressed in the vascular system; semaphorin 3E–plexin D1 signalling controls endothelial cell positioning and the patterning of the developing vasculature in the mouse, and its loss in zebrafish disorganises vessel pathfinding [6]. This vascular role gives the gene a plausible biological link with the vascular disruption hypothesis, without demonstrating it. REV3L, at 6q21, encodes the catalytic subunit of DNA polymerase zeta, involved in the replication of damaged DNA [42]. One of the three carriers of REV3L variants had pectoral agenesis [7]. In 2022 a boy with Poland–Möbius, the son of consanguineous parents, was described as heterozygous for NM_015103.3(PLXND1):c.2890G>A p.(Val964Met) (NP_055918.3; NC_000003.12:g.129572889C>T in GRCh38), reported in the article on transcript NM_015103.2 [5, 43]. The variant was inherited from the mother, who did not have the phenotype, and is classified in ClinVar as of uncertain significance (VUS), last evaluated in November 2022 [5, 44]. The same patient had a synonymous variant, c.4677C>T p.(Asn1559=), regarded as likely benign by the authors [5]. OMIM records the possible association between PS and PLXND1 as pending confirmation and, regarding this case, comments that penetrance would have to vary greatly among carriers or that other variables would contribute to the phenotype [1, 6]. In the 2022 review, only 14 cases of Poland–Möbius had a complete description and genetic study: karyotype or microarray was normal in 11, and the others had a gain at 3q23 (with dextrocardia), a deletion including REV3L at 6q21 and a t(1;11) translocation [5]. The translocation t(1;11)(p22;p13), described by Donahue in 1993, accompanied Möbius, PS, cleft palate, dextrocardia and mandibular hypoplasia [11].

2.8. Phenocopies and entities with a known genetic cause

Pectoral hypoplasia is not exclusive to PS. In the systematic review of 627 patients, 57% of those with pectoral malformation, hand malformation and at least one other anomaly had one or more features compatible with another syndrome, some with a recognised genetic cause [32]. Carey-Fineman-Ziter syndrome (OMIM 254940), an autosomal recessive congenital myopathy caused by hypomorphic variants in MYMK (myomaker, 9q34.2, OMIM 615345), the gene for a transmembrane protein required for the fusion of myoblasts into multinucleated myofibres [45], combines marked facial weakness with a distinctive pattern, and PS may be part of the picture; the mechanism is a defect of myoblast fusion [10, 46]. Biallelic variants in STAC3, the cause of Native American myopathy, were found in a family from Qatar with suspected Carey-Fineman-Ziter (homozygous NM_145064.3(STAC3):c.851G>C p.(Trp284Ser)) and in a Puerto Rican family with suspected Möbius and a history of malignant hyperthermia (compound heterozygous for c.851G>C p.(Trp284Ser) and c.763_766del p.(Leu255IlefsTer58)); screening of STAC3 in 12 patients with Carey-Fineman-Ziter and 50 with Möbius or congenital facial weakness was negative [43, 47]. In craniofrontonasal dysplasia, X-linked and caused by variants in EFNB1, Poland anomaly occasionally occurs in affected females [48]. In Becker naevus syndrome, caused by postzygotic ACTB variants in somatic mosaic state, the naevus is associated with unilateral breast hypoplasia or with cutaneous, muscular or skeletal defects on the same side; OMIM describes a 13-year-old girl with unilateral hypoplasia of the left breast and pectoral muscle and a postzygotic ACTB variant, and the androgen-dependent naevus is barely visible in women and prepubertal boys [49]. A de novo 1.5 Mb duplication at Xp22.31 has also been described in a child with left-sided PS, strabismus, hypoplasia of the optic nerves and chiasm, corpus callosum anomalies, ectopic neurohypophysis, pyelectasis and neurodevelopmental delay [21].

2.9. Pathophysiology of the manifestations

The sternocostal head of the pectoralis major is the portion always affected; the clavicular head, pectoralis minor, serratus anterior, latissimus dorsi, deltoid and external oblique may be absent or hypoplastic in variable proportions [10, 35]. Sprengel deformity results from absence of the upper portion of the serratus anterior, which leaves the scapula elevated [10]. The ribs most often involved are the 3rd to the 5th; the sternal ends of aplastic ribs may fuse and the sternum may be rotated [35]. Agenesis of anterior rib segments creates an area without bony or muscular support that behaves as an open thorax, with paradoxical breathing and, sometimes, lung herniation [10, 28]. The dextrocardia described in left-sided PS corresponds to a mechanical dextroposition: in the Italian series of 122 patients, all 14 patients with dextrocardia had left-sided PS with partial agenesis of at least two ribs, none had situs inversus, and all patients with partial agenesis of two or more ribs had dextrocardia [19]. The authors interpreted the displacement of the heart to the right as a consequence of the lack of rib support during development, and not as a laterality defect [19]. Hypoplasia of the subcutaneous tissue and absence of ipsilateral axillary hair accompany the muscle defect and contribute to the visible asymmetry [2].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts

The available clinical data come from series from reference centres, an old population-based series and a systematic review of the literature. None of these sources follows a birth cohort into adulthood, and surgical series tend to include the most severe forms.

The Genoa series of 245 patients, published in 2018, extends the 2012 cohort of 240 patients and is the largest assessed with a single protocol (paediatric surgeon, plastic surgeon, hand surgeons and orthopaedist, geneticist and psychologist; ultrasound of the pectoral region, echocardiogram, abdominal ultrasound and chest radiograph, with upper-limb radiograph and CT only when indicated) [18]. The inclusion criterion was total or partial absence of the pectoralis major. The pectoralis minor was absent or hypoplastic in 94.1%, the nipple was hypoplastic or absent in 67.2% and all girls had hypoplasia or absence of the breast, reliably evident only after thelarche. The male:female ratio was 1.7:1 and the right:left ratio 1.6:1; the text of the article gives 66.3% boys, but the table, consistent with 155 of 245, gives 63.3%. Patient age ranged from 1 to 57 years (median 11.2), and diagnosis had been made between the first day of life and 43 years [18]. The data come from a reference centre and a patient association, which may enrich the series for more visible forms.

3.2. Muscles and soft tissues of the chest wall

The constant manifestation is agenesis or hypoplasia of the pectoralis major, which always affects the sternocostal head [10]. In the Turkish series, absence was total in 71.6% of patients and limited to the sternocostal head in 28.3% [15]; in the Italian series of 120 patients, 51 had agenesis and 69 hypoplasia [7]. The pectoralis minor is missing in a variable proportion, and the latissimus dorsi is involved in a minority, a relevant finding because it limits the use of this muscle in reconstruction [1, 10]. Orphanet classifies as very frequent (80–99% of patients) thoracic asymmetry, aplasia of the pectoralis major, absence of subcutaneous fat and aplasia or hypoplasia of the breast and nipple, and as frequent (30–79%) absence of the pectoralis minor [2]. Ipsilateral axillary hair is sparse, absent or ectopic [10]. Without bony involvement, the defect may go unnoticed for years, particularly in prepubertal boys; severe forms are recognised at birth [10].

3.3. Breast and nipple–areola complex

Hypoplasia or aplasia of the breast, areola and nipple is an additional diagnostic criterion [10]. The nipple–areola complex (NAC) is typically hypoplastic and displaced cranially; in the 2024 adolescent series, all patients with displacement greater than 2 cm had the NAC more than 8 cm above the contralateral position before treatment [16]. Among the 28 boys in this series, 6 had NAC hypoplasia with displacement of less than 2 cm (N1), 21 displacement greater than 2 cm (N2) and 1 absent NAC (N3); among the 24 girls, 1 was N1, 18 N2 and 5 N3, and 16 had breast hypoplasia (B1) and 8 amastia (B2) [16]. The true extent of the breast deformity becomes evident after puberty, when the contralateral breast develops [51]. In nine girls of the same series, the contralateral breast was tuberous and was corrected during the same surgical pathway [16].

3.4. Rib cage and sternum

Pectus excavatum or carinatum occurred in 21 of the 120 patients of the CNV series, and rib anomalies in 10 [7]. In the series of operated adolescents, 25 had only muscle and soft tissue defect (T1), 10 had sternal deformity or pectus (T2: 4 excavatum, 4 carinatum and 2 of the Currarino-Silverman type), 2 had rib aplasia (T3) and 15 had combined muscle, sternal and rib defect (T4) [16]. Rib aplasia may cause paradoxical breathing, lung herniation and, in extensive defects, cardiac pulsation visible through the wall [10, 28]. Respiratory symptoms are uncommon [10]. Clavicular hypoplasia is rare [7, 10]. In the Genoa series of 245 patients, rib agenesis (rib without articulation with the sternum) occurred in 40 patients (16.3%) and rib hypoplasia (rib deformed or thinner but in continuity with the sternum) in 20 (8.2%); the most affected ribs were the 3rd (39.4%) and the 4th (26%), and among patients with a rib defect 29.6% had one rib affected, 46.3% two, 18.5% three and 5.6% four, with no case of more than four. Pectus excavatum occurred in 10.3%, carinatum in 8.6% and the mixed form in 6.5%, and 74.6% had no sternal deformity [18].

3.5. Upper limb

The spectrum ranges from a hypoplastic but functional hand to severe symbrachydactyly with one or more absent digits, and some patients have no hand malformation [10]. Upper-limb anomalies were present in 57 of the 120 Italian patients: 24 with classical brachysyndactyly and 28 with hypoplasia of the upper limb or hand [7]; in the systematic review, upper-limb deformity affected 58% of published patients [32]. The most constant radiological finding, besides cutaneous syndactyly, is aplasia or hypoplasia of the middle phalanges of the 2nd to 5th digits (brachymesophalangy), with lesser involvement of the thumb; in severe forms, the proximal and distal phalanges and the metacarpals are also hypoplastic or absent [3]. Mild shortening of the forearm bones and underdevelopment of the arm muscles, detectable only by measurement, proximal radioulnar synostosis and Sprengel deformity may coexist [10, 50]. It is estimated that about 10% of patients with syndactyly of the hand have PS [14]. In a kinematic study with inertial sensors, shoulder range of motion did not differ between the affected and the healthy side; all patients had a positive posterior instability test, and the affected side showed greater mediolateral scapular rotation and earlier retraction during flexion and abduction, with reduced scapular tilt in those under 18 years [52]. The first case of thoracomelia, with an accessory digit on the ipsilateral chest wall, associated with pectoral hypoplasia and upper-limb deficiency, was described in 2025 [53].

3.6. Heart

Dextrocardia is the most frequently described cardiac anomaly, and its relationship with left-sided PS and with agenesis of two or more ribs has been quantified: 14 of 122 patients (11.5%) in an Italian series, without situs inversus; three of these had simple congenital heart disease [19, 35]. In the series of 245 patients, dextrocardia occurred in 18 of the 180 with data (10%), only in forms with a rib defect: in 52.2% of the thoracic variant and in 24% of the complete form, and never in the minimal or upper-limb forms; heart defects, present in 7.5%, were mild and none required treatment [18]. Atrial septal defect and other isolated heart defects have also been described [7, 10]. The Oxford Desk Reference recalls that 15% of children with limb reduction defects have congenital heart disease, a figure that refers to these defects as a whole and not to PS [33].

3.7. Kidneys and genitourinary tract

Orphanet classifies renal hypoplasia as frequent (30–79%) and records as occasional (5–29%) cryptorchidism, hypospadias, ureterocele, vesicoureteral reflux and duplication of the collecting system [2]. The consensus describes genitourinary malformations (renal agenesis or ectopia, vesicoureteral reflux, cryptorchidism) as rare [10]. The discrepancy arises because Orphanet annotations are frequency classes assigned without a published denominator, whereas the consensus is based on the centres' experience; none of the sources consulted presents a frequency measured in a cohort screened by ultrasound. In the British Columbia series, an ipsilateral undescended testis was one of the infrequent associations [13].

3.8. Spine and shoulder girdle

Sprengel deformity is the most common accompanying anomaly, present in 18 of 113 Turkish patients (15.9%) [10, 15]. Hemivertebrae, vertebral fusions and scoliosis occur in a minority [10, 14]. Scoliosis may be congenital, due to vertebral malformation, or develop during growth because of chest wall asymmetry, which justifies spinal monitoring until the end of growth [10, 31].

3.9. Nervous system, face and other associations

In Möbius sequence, associated PS was found in 4 of 37 Dutch patients (11%) and is estimated at about 20% in dysmorphology textbooks; in a Swedish series of 25 patients with Möbius, 2 had Poland anomaly [11, 20, 34]. The reverse overlap is much smaller: in the series of 120 Italian patients with PS there was a single case of Poland–Möbius, a 9-month-old child with right facial and VI and VIII cranial nerve palsy, Pierre Robin sequence and right upper-limb hypoplasia [7]. Isolated coexistence has been described with Adams-Oliver syndrome, the oculo-auriculo-vertebral spectrum (Goldenhar syndrome), Klippel-Feil anomaly and frontonasal dysplasia [1, 10]. There are reports of microcephaly, Dandy-Walker malformation, craniofacial dysplasia and, in 2025, an atretic cephalocele in a 2-month-old child, the first association described with a neural tube closure defect [35, 54]. Orphanet also records as occasional, without a denominator, diabetes mellitus, myopia, retinal hamartoma, congenital diaphragmatic hernia and hepatic anomalies; the consensus mentions malformations of the liver and biliary tract [2, 10]. Psychomotor development is normal in isolated PS [10].

3.10. Neoplasms

Cases of breast, lung and gastric cancer, myosarcoma, Hodgkin and non-Hodgkin lymphomas, extragonadal seminoma and acute leukaemia have been published in patients with PS [2, 35]. The breast cancer cases described occurred mainly in middle-aged or older women and on the affected side, and a 2024 review states that the incidence would be higher than in the general population, while acknowledging that not all authors agree [35]. The evidence is limited to case reports and narrative reviews; there are no cohort studies or risk estimates, and the association has not been demonstrated. In the Genoa series of 245 patients, mostly paediatric, there were no cases of neoplasia, and the authors concluded that paediatric tumours do not appear more frequent in PS than in the general population; the series provides no information on risk in adulthood [18]. The absence of muscle over the breast makes reconstruction after mastectomy more difficult, and radiotherapy is delivered without the usual muscle protection [35].

3.11. Natural history by age

PS is congenital and non-progressive: the muscle defect does not worsen, but its perception changes with growth [10]. In the newborn and infant, forms with symbrachydactyly, rib defect or obvious asymmetry are recognised; in the series of 57 patients and carers in the Italian survey, the diagnosis was made at birth in 31.6% and in the 1st year of life in 40.4%, although the signs had appeared at a mean of 4 months [17]. In childhood, the problems mainly concern the hand and upper-limb function [10]. Puberty is the period in which breast asymmetry in girls and pectoral asymmetry in boys become most visible, and it is also the period of greatest body-image distress [51, 55]. The mean age at diagnosis was about 14 years in that survey, and 12.3% of participants made their own diagnosis [17]. In adulthood, most patients are healthy, and the main concern is aesthetic [3, 14]. The exception is forms with an extensive rib defect, in which a case published in 2026 describes a 62-year-old woman with dyspnoea since childhood and progressive hypercapnic respiratory failure, with an elevated right hemidiaphragm, left pulmonary hypoplasia and absence of the left pectoral muscles, diagnosed only at that age [56]. In women, breast reconstruction changes with age, pregnancy and weight fluctuations, which requires corrections throughout life [10, 51]. The data describing the treated disease come from surgical series with mean follow-up of 2 to 6 years [16, 51].

3.12. Bilateral form and partial forms

The bilateral form is rare and its existence as an entity is debated. In the Turkish series, 8 of 113 patients (7%) were classified as bilateral [15]; in the 2024 adolescent series, one patient had T4 on the left and T1 on the right [16]. In the face of presumably bilateral PS, the consensus requires a more extensive differential diagnosis, including skeletal dysplasias of the rib cage [10]. At the other extreme, isolated absence of the pectoralis major with or without breast hypoplasia is regarded as the minimal form of the spectrum, and relatives of patients may have only symbrachydactyly or breast asymmetry [1, 9, 14].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

In the newborn, infant and child, the Italian consensus recommends suspecting PS in the presence of asymmetric pectoral hypoplasia accompanied by any rib cage anomaly, or of isolated unilateral pectoral anomalies [10]. The presence of an upper-limb defect, whether symbrachydactyly, syndactyly with short digits or a transverse defect, should always prompt examination of the pectoral muscle and chest on the same side [33, 37]. The question «is there shortening of any digit, a symbrachydactyly?» is part of the examination of any syndactyly [37]. A chest radiograph with a unilateral hyperlucent hemithorax may be the first clue to an unrecognised pectoral defect [3, 10]. In adolescents and adults, suspicion arises in the presence of unexplained muscle hypoplasia with thoracic asymmetry, unilateral hypoplasia or agenesis of the breast or nipple, or an ipsilateral hand anomaly [10]. Because the extent of the breast deformity becomes evident only after puberty, some patients are diagnosed only in adolescence or adulthood [17, 51].

4.2. Examination manoeuvre

The pectoral defect becomes evident when the patient is asked to press the palms of the hands against each other, with the arms in front of the body, which makes the asymmetry of muscle contraction visible [10]. The examination also includes the breast, areola and nipple, rib cage, clavicle, axillary hair, scapula and the whole upper limb, from shoulder to hand [2, 10].

4.3. Warning signs

Some findings indicate a more complex phenotype or a diagnostic alternative. Congenital facial palsy, especially if associated with an ocular abduction deficit, points to Poland–Möbius sequence and requires assessment of swallowing, feeding and the airway, because these infants may aspirate and need tube feeding [5, 20]. In craniofrontonasal dysplasia, hypertelorism and craniosynostosis accompany Poland anomaly [48]. Generalised muscle weakness, hypotonia or marked facial weakness suggest a congenital myopathy, such as Carey-Fineman-Ziter syndrome or STAC3 myopathy [10, 47]. Aplasia cutis of the scalp suggests Adams-Oliver syndrome [33]. Bilaterality, symmetric limb anomalies, short stature or intellectual disability move the picture away from isolated PS and justify assessment by a dysmorphology specialist [10, 32, 33].

4.4. Emergency signs

Isolated PS rarely causes urgent situations. Exceptions are paradoxical breathing with respiratory distress due to extensive rib agenesis, lung herniation, feeding difficulties and aspiration in the infant with Poland–Möbius, and cardiac or pulmonary compression due to severe pectus excavatum [5, 10, 35]. Chronic respiratory failure in an adult with unilateral chest deformity should also suggest undiagnosed PS [56]. During surgical correction of pectus excavatum, passage of the introducer may compress the heart and cause severe ST-segment depression and bradycardia [28].

4.5. Newborn screening and prenatal detection

There is no newborn screening for PS. Prenatal detection is rare: the anomaly scan shows only severe bony manifestations of the hands or rib cage, and the findings are non-specific [10]. A fetal case published in 2026 showed right rib hypoplasia with diaphragmatic protrusion, and the authors regarded prenatal diagnosis as extremely difficult [57]. The limbs are visible on ultrasound at 13–14 weeks, but the digits are rarely visualised clearly before 20 weeks [33].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

Since no gene has been identified, the diagnosis is clinical and rests on pattern recognition and exclusion of alternatives [10]. The 2020 consensus was developed by 35 Italian experts (clinical and molecular genetics, paediatrics, plastic, thoracic and hand surgery, psychology, radiology and physiotherapy) through a modified Delphi method, with a literature search from 1990 to 2019, two survey rounds and a face-to-face meeting in Modena in October 2019; of the 91 recommendations formulated, most are good practice by consensus [10]. The grades used are «strong literature», «modest literature» and good clinical practice (GCP) without relevant literature.

Source: Italian AISP/ERN-BOND consensus [10].

5.2. Clinical assessment

The examination looks for the pectoralis major defect, anomalies of other muscles (pectoralis minor, serratus anterior, latissimus dorsi, deltoid), of the rib cage (agenesis or hypoplasia of rib segments, pectus carinatum or excavatum, clavicular hypoplasia, lung herniation), of the breast region and of the upper limb, asymmetric reduction of axillary hair and other skeletal anomalies, such as Sprengel deformity, radioulnar synostosis, hemivertebrae and vertebral fusions [10]. In the assessment of any limb reduction defect, the Oxford Desk Reference includes a three-generation pedigree, maternal diabetes, vaginal bleeding between 5 and 11 weeks, drug exposure (misoprostol, retinoids, cocaine, valproate), twinning and invasive procedures, as well as examination of the four limbs, scalp, tongue and mandible, face and eyes (for a VI or VII nerve palsy, easily missed in the infant), heart and the hands and feet of the parents [33]. Photographic records and a diagram of the defects help follow-up and surgical planning [33].

5.3. Musculoskeletal ultrasound

Ultrasound is the first-line, and often the only, investigation to confirm the suspicion and assess severity, because it is available, uses no radiation and is cost-effective (R3.10, strong, 92.3%) [10]. It is performed with a high-frequency probe and musculoskeletal preset, bilaterally and comparatively, and assesses the three heads of the pectoralis major (clavicular, sternocostal and abdominal) in sagittal and transverse planes, the pectoralis minor, the subcutaneous tissue and the breast (R3.19, strong, 100%) [10]. It allows the pectoralis major to be classified into three classes: total agenesis; agenesis of the sternocostal portion with a normal costoclavicular component; partial agenesis of the sternocostal portion with a normal costoclavicular component (R3.14, strong, 90.9%) [10]. The consensus proposes a four-view protocol:

Source: Italian consensus, Table 4 [10].

Distinguishing the three heads of the pectoralis may be difficult for those without musculoskeletal experience [35]. In the hands of a radiologist with that experience, ultrasound also maps the hand muscles, which is useful for surgery and rehabilitation in children poorly suited to MRI [10]. In the Genoa adolescent series, the clinical diagnosis was always confirmed by musculoskeletal ultrasound [16].

5.4. Radiography, computed tomography and magnetic resonance imaging

A chest radiograph is performed routinely for a gross assessment of the rib cage and heart (R3.16, strong, 88.9%), although it is neither specific nor necessary for the diagnosis (R3.20) [10]. It shows hyperlucency of the affected hemithorax, rib and sternal irregularities and cardiac position [3, 35]. A unilateral hyperlucent hemithorax has other causes, pleural, parenchymal, pulmonary vascular, central airway, mediastinal and technical (patient rotation, off-centring) [10]. Computed tomography (CT) and MRI show the absence of the pectoralis major and neighbouring anomalies better, but are not used routinely in the diagnostic phase (R3.18) [10]. CT is reserved for rib cage anomalies with a surgical indication (R3.11) and for complex deformities, in which it details the bony anomalies and vascular relationships, with three-dimensional reconstruction useful for planning and, more recently, for the design of custom implants (R3.23) [10, 16]. The consensus text mentions contrast-enhanced CT for vascular study, whereas R3.11 indicates non-contrast CT for the rib cage; the two indications correspond to different questions. MRI has limited indications, mainly when ultrasound is inconclusive (R3.15), provides most of the presurgical information without radiation and requires dedicated sequences because of respiratory movements and, in young children, anaesthesia [10]. A 2024 review aimed at thoracic surgeons favours CT for bone and MRI for soft tissues and states that ultrasound has lost importance; this position diverges from the consensus, which keeps ultrasound as first line, and both sources agree in reserving low-dose CT for surgical candidates, to limit radiation in young people and women of reproductive age [10, 35]. A complete radiological study of the hands, forearms, arms and scapulae is justified only in selected patients with complex anomalies and in surgical planning (R3.21, GCP) [10].

5.5. Assessment of associated anomalies

After diagnosis, the consensus recommends ultrasound to exclude structural intra-abdominal, renal and cardiac anomalies (R1.3, modest, 100%) and, as baseline radiological assessment, pectoral ultrasound, chest radiograph, echocardiography and abdominal ultrasound, with other investigations according to the phenotype (R3.13, strong, 100%) [10]. For each new patient under 18 years, the initial assessment includes a paediatric thoracic surgeon, chest radiograph, echocardiography, genetic counselling, orthopaedic assessment, a plastic surgeon for pre-adolescents and adolescents and abdominal ultrasound (R13.82, strong, 87.5%) [10]. In infants and young children with a limb reduction defect, the Oxford Desk Reference advises an echocardiogram and electrocardiogram [33]. Radiographs of both upper limbs document the hand defect and allow it to be distinguished from other forms of brachydactyly [33, 58]. In the presence of signs of Möbius, the assessment includes neuro-ophthalmological examination and brainstem MRI, which may show malformations of the pons, cerebellum and midbrain [3, 20].

5.6. Classifications

Several classifications describe different parts of the phenotype and are not equivalent. The consensus adopts three: the global classification into minimal (pectoral defect only), partial (with thoracic or upper-limb variant) and complete forms (R8.42, strong, 88.9%), proposed by the Genoa group in 2018; the TBN classification for the thoracic defect (R8.43, strong, 100%); and the Catena classification for the hand and upper limb (R9.53, strong, 100%) [10, 18]. The consensus does not transcribe the operational boundaries between the partial and complete forms, which appear in the original 2018 proposal: type 1 or minimal form, isolated pectoral defect, without rib or upper-limb anomaly; type 2 or partial form, pectoral defect with rib or upper-limb anomaly, divided into 2a (upper-limb variant, without rib anomaly) and 2b (thoracic variant, without upper-limb anomaly); type 3 or complete form, pectoral defect with rib and upper-limb anomalies [18]. In the series of 245 patients, form 2a was the most frequent (106; 43.3%), followed by the minimal form (79; 32.2%), the complete form (31; 12.7%) and 2b (29; 11.8%). The types differed: dextrocardia occurred only in forms 2b and 3, renal malformations were concentrated in form 2a (11.9%), mild heart defects occurred in forms 3 (12%) and 2a (10%) and not in the minimal form, and diagnosis in the 1st year of life was made in 92.9% of complete forms, versus 19.7% of minimal forms [18]. Upper-limb anomalies (56% of the series) were classified by the eight Catena groups: among the 137 patients with an anomaly, the most frequent groups were symbrachydactyly with five functional digits and a hypoplastic hand without morphological or functional anomaly [18].

The TBN classification (thorax, breast and nipple), proposed in 2016 and applied by the Genoa group to 100 patients, found T1 in 47% and N2 in 74%, with B1 more frequent than B2 in females [59]. It is dynamic: treatment may reclassify a T4 as T1 [16]. Growth also changes the category: a T1 patient may develop pectus carinatum in the prepubertal phase and become T2, a T3 may develop pectus excavatum or mixed pectus and become T4, the nipple–areola complex may move progressively and rise in N, and the B parameter can be assessed in girls only after puberty; the authors therefore treat TBN as a description of the defect at a given moment [18].

Source: Romanini 2016 and 2024 [16, 59].

The Catena classification is based on 175 patients and covers the whole upper limb [10, 50]:

Source: Italian consensus, R9.53–R9.54 [10].

For breast reconstruction in adolescents from 15 years and in adults, the Salzburg group uses a modified version of the 2009 Ribeiro classification [51]:

Source: Mahrhofer 2021, Table 1 [51].

Other thoracic classifications used in the surgical literature are that of Foucras, with three grades (I, hypoplasia of the pectoralis major or breast with mild asymmetry; II, aplasia of the pectoralis major and hypoplasia of other muscles; III, muscle aplasia with major rib and sternal deformities), and that of Stylianos, with four grades (1, hypoplasia of the pectoral muscles; 2, absence of the sternocostal head; 3, total absence of the pectoralis major or of both pectoral muscles; 4, hypoplasia or absence with skeletal anomalies); for the hand there are the Gausewitz and Al-Qattan classifications, based on the presence, length and shape of the digits and the size of the hand [35]. In 2022, a Spanish group proposed a classification based on 74 cases [60]. The coexistence of these classifications makes comparison between series difficult; TBN is the one used by AISP and the Italian centres [10, 35].

5.7. Genetic testing: indication and limits

There is no routine laboratory test to confirm PS, and cytogenomic, molecular and exome sequencing investigations should be limited to the most complex cases (R7.36, modest, 100%) [10]. The Oxford Desk Reference indicates genomic analysis (array, panel, exome or genome) when other features suggest a chromosomal or syndromic diagnosis, and single-gene testing when the phenotype points to a syndrome with a known gene, such as Holt-Oram syndrome [33]. In practice, the scenarios in which a genetic study is justified are an atypical phenotype with features of another syndrome, association with intellectual disability or other malformations, muscle or facial weakness suggestive of congenital myopathy (MYMK, STAC3), craniofacial features of craniofrontonasal dysplasia (EFNB1) and familial recurrence [10, 32, 46–48]. In the Italian series of 120 patients, array-CGH found rare CNV in 14 patients, none recurrent and mostly inherited from unaffected parents, which means that a positive result rarely explains the phenotype [7]. A negative result does not exclude PS, which remains a clinical diagnosis, nor does it exclude somatic mosaicism or a cause not detectable by the techniques used [10]. When a test finds a variant in a candidate gene, such as PLXND1 in Poland–Möbius, the report should state the gene, the transcript with version (for example, NM_015103.3), the HGVS (Human Genome Variation Society) nomenclature, the zygosity, the classification according to ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria and familial segregation; the p.(Val964Met) variant, inherited from an unaffected mother and classified as VUS, illustrates that the presence of a rare variant in a candidate gene does not establish causality [5, 43, 44].

5.8. Prenatal and preimplantation diagnosis

Prenatal suspicion is sometimes possible as an incidental finding on the anomaly scan, when there are severe bony manifestations of the hands or rib cage, and should be confirmed clinically after birth; when the parents are affected, no further radiological investigations are indicated in utero (R3.12, GCP, 100%) [10]. Prenatal ultrasound is limited by the difficulty of appreciating thoracic asymmetry and by fetal movements, especially in low-risk pregnancies [10]. As there is no known molecular basis, there is no test applicable to prenatal or preimplantation diagnosis, and counselling is given without laboratory support (R7.35, strong, 100%) [10].

5.9. Diagnostic algorithm

The 2018 Genoa flowchart, which predates the consensus, also starts from clinical examination and uses ultrasound of the pectoral region to distinguish partial from total absence of the pectoralis major, assess the pectoralis minor and neighbouring muscles and detect cartilage anomalies; the authors note a learning curve for distinguishing the three portions of the muscle by ultrasound. It differs from step 4 of the table on one point: it reserves the chest radiograph for clinical suspicion of rib agenesis, in which it shows the defect and any shift of the heart to the right, and CT for severe rib cage deformities and patients who are to undergo surgery; it keeps echocardiography and abdominal ultrasound in all patients, because cardiac and renal anomalies, although infrequent and mild, can only be excluded by examination [18].

6. Differential Diagnosis

6.1. Clinical scenarios

The literature on the differential diagnosis of PS is scarce: of the 33 articles found by the consensus with the terms «Poland» and «differential diagnosis», only four discussed the topic [10]. The consensus organises the differential into scenarios: unilateral PS without skeletal or limb anomalies; unilateral PS with these anomalies; presumably bilateral PS; complex phenotypes («PS plus»); and hyperlucent hemithorax on the radiograph [10]. In the typical patient, with isolated unilateral pectoral hypoplasia, with or without hypoplasia of the breast and nipple, the most common alternative diagnoses are thoracic asymmetry due to scoliosis or to sternal, rib or vertebral anomalies, isolated congenital asymmetry of the breast, areola or nipple, especially in women, sequelae of trauma or surgery, and unilateral anomalies of the diaphragm [10]. In hand defects, identification of the ipsilateral pectoral defect, necessary and characteristic of PS, separates it from the other malformations [3, 10].

6.2. Comparative table

6.3. Möbius sequence and Poland–Möbius

Since the 2007 Moebius Syndrome Foundation conference, Möbius sequence has been defined by non-progressive congenital facial weakness with limited abduction of one or both eyes; deafness, other cranial nerve palsies and motor, orofacial, musculoskeletal and neurodevelopmental problems may coexist [11]. It is regarded as a hindbrain malformation, and most cases are sporadic [3, 11]. Birth prevalence is estimated by Orphanet at less than 1/1,000,000 in Italy, and a 2022 review article cites about 1/50,000 live births; in Brazil, the sequence has been described in the context of misoprostol use as an abortifacient [5, 12, 73]. In the Swedish series of 25 patients, there were limb malformations in 10, Poland anomaly in 2, hypodontia in 7, cleft palate in 4 and hearing impairment in 5, and 6 had autism spectrum disorder [34, 74]. In Poland–Möbius, assessment of the palsies, feeding and the airway dominates the first year of life; differential diagnosis from hereditary congenital facial palsy, restricted to the VII nerve, and from recessive congenital myopathies is essential, because these carry a 25% recurrence risk and, in the case of STAC3, documented susceptibility to malignant hyperthermia [11, 46, 47]. Carey-Fineman-Ziter is distinguished by its own pattern of congenital myopathy with marked facial weakness; clubfoot and muscle weakness should raise this hypothesis [10, 34]. OMIM now describes it as a slowly progressive congenital myopathy due to defective myoblast fusion, with hypotonia, Möbius sequence, Pierre Robin complex and motor delay, and records a patient with unilateral absence of the pectoralis major and ulnar deviation of the hand interpreted as Poland sequence; there is a second form, CFZS2, due to variants in MYMX [61].

6.4. Upper-limb defects

The brachysyndactyly of PS is sometimes mistaken for a terminal transverse defect; the doubt is resolved by examining the chest [10]. In the limb anomaly classification of the EUROCAT network (European Surveillance of Congenital Anomalies), the hand defect of PS is a transverse defect, distinct from longitudinal absences and split hand [3, 33]. Ectrodactyly is characterised by deficiency of the distal central rays, with a two- or three-digit hand and a cleft that may reach the carpus [10]. Brachydactyly A1 has short middle phalanges like PS, but is always bilateral [58]. In amniotic band syndactyly, the fingertips are joined and a probe can pass proximally between the digits, which does not happen in malformative syndactylies [37]. A history of exposure to thalidomide, misoprostol or invasive procedures in the first trimester points to embryopathies and disruptions [33, 69]. The Temtamy and McKusick classification distinguishes non-syndromic syndactylies, such as type I (fingers 3–4 and toes 2–3, bilateral in half of cases), HOXD13 synpolydactyly and GJA1 type III (fingers 4–5, oculodentodigital dysplasia), from the syndactyly with shortened digits of PS [37].

6.5. Thoracic and breast asymmetry without pectoral defect

Isolated congenital breast asymmetry is common in women and is distinguished by the sonographic integrity of the pectoralis major [10]. Localised lipoatrophy, morphoea, Parry-Romberg syndrome and Becker naevus syndrome may reduce the soft tissues of the chest wall, and a case of overlap between PS and localised lipoatrophy has been published [10]. Becker naevus syndrome deserves particular attention, because it may include hypoplasia of the pectoral muscle and breast on the same side; the pigmented, hairy patch, which becomes more pronounced in adolescence and is less visible in girls, and the histology with bundles of smooth muscle guide the diagnosis, confirmed by a postzygotic ACTB variant in lesional tissue [49]. Parry-Romberg progressive hemifacial atrophy is an acquired, progressive soft tissue atrophy, related by several authors to localised scleroderma, and is distinguished by its course [70]. Scoliosis and rib or sternal anomalies produce asymmetry without a muscle defect, and unilateral diaphragmatic defects may simulate an asymmetric hemithorax [10].

6.6. Presumably bilateral form

In the presence of bilateral pectoral defects, the consensus recommends considering skeletal dysplasias of the rib cage (R5.25, modest, 77.8%) and requesting assessment by a dysmorphology specialist and a whole-body skeletal radiograph [10]. The Karnak case, published in 1998 as bilateral PS, was reclassified as a thoracic dysplasia [1, 10]. In the systematic review of 627 patients, more than half of those with a complex phenotype had features of an alternative syndrome, which justifies diagnostic reassessment of atypical phenotypes [32].

7. Treatments and Risk Management Strategies

7.1. General principles and evidence base

There is no aetiological treatment or pharmacological therapy targeted at PS; major anomalies are treated like the equivalent isolated malformations [10]. The aims are to preserve and improve the function of the hand and upper limb, protect the thoracic organs when the rib cage is deficient, correct thoracic and breast asymmetry when the patient so wishes, and prevent the psychological consequences of bodily difference [10]. Without functional limitations, surgery is not necessary, and the patient may opt for an aesthetic intervention (R14.88, strong, 70%) [10]. The evidence base is the 2020 Italian consensus, whose recommendations are mostly good practice by consensus, and retrospective single-centre surgical series (level IV); there are no randomised trials [10, 16, 51]. A 2025 systematic review, with 77 included studies, concluded that there is no gold standard for chest and breast reconstruction [75].

7.2. Organisation of care

The consensus recommends a multidisciplinary team coordinated by a case manager, with a paediatric or thoracic surgeon, plastic surgeon, orthopaedist, hand surgeon, radiologist, geneticist, psychologist, cardiologist, ophthalmologist and other specialists according to the phenotype (R14.86, strong, 100%) [10]. Thoracic surgery in children should be planned and performed by paediatric surgeons, whose role includes long-term follow-up of thoracic symmetry, ribs and sternum (R13.80–R13.81) [10]. Early assessment optimises treatment and has psychological advantages (R8.44), and combined thoracic and plastic treatment reduces the number of procedures (R8.46) [10]. Close links with national and international patient associations are also a strong recommendation (R14.87) [10]. In an Italian survey, patients diagnosed outside their own region were more likely to have a late diagnosis (odds ratio, OR, 4.10; 95% confidence interval, 95% CI, 1.10–18.05) and to forgo treatment (OR 11.59; 95% CI 2.46–84.32), and living outside the two regions with a dedicated diagnostic and therapeutic pathway was associated with diagnosis outside the region (OR 8.17; 95% CI 1.69–60.72) [17].

7.3. Hand surgery

Hand treatment begins with the mandatory examination of the whole upper limb, including shoulder and elbow (R9.47), and with planning adapted to the type of deformity according to the Catena classification (R9.48, R9.53) [10]. Types I and II do not need surgery; types III and, particularly, IV and V have a surgical indication (R9.54) [10].

Source: Italian consensus, Table 9 [10].

Skin grafts, when needed, are harvested from the volar wrist or the groin, under an occlusive dressing; the consensus text allows the first dressing change between 2 and 3 weeks, whereas recommendation R9.59 sets it at 3 weeks, and the dressing is changed earlier if there is infection, exudate or inadequate care [10]. Non-vascularised free phalangeal transfer is used when a proximal phalanx is present, to increase the length of the ray; microvascular transfer of a toe is the only option in the peromelic hand or congenital metacarpal amputation [10]. Parents accept free phalangeal transfer more readily, although the functional and aesthetic result is inferior [10]. Even with severe malformations, appropriate education allows manual skills to be acquired [10].

7.4. Chest wall: indications and timing

Thoracic surgery is not always necessary. The indications are severe anomalies of the anterior wall (pectus excavatum, carinatum or both) and of the ribs (rib agenesis), for aesthetic or functional reasons, the latter being paradoxical breathing due to significant rib agenesis and cardiac or pulmonary compression due to pectus excavatum [10, 35]. Respiratory symptoms are uncommon, and the lack of protection due to rib agenesis does not by itself indicate thoracoplasty in childhood (R8.38, strong, 57.1%); the consensus authors found no reports of traumatic complications attributable to rib agenesis in PS [10]. In general, there is no need to operate before 12–13 years, and the preferred age for chest reconstruction is 14–15 years; non-absorbable materials should be avoided before 12 years (R8.39, modest, 80%) [10]. In pectus excavatum and carinatum, the decision is individual, and without respiratory symptoms intervention should be deferred at least until early adolescence, close to the end of chest wall growth (R8.41, strong, 57.1%) [10]. A 2024 review summarises the strategy: in mild forms, single-stage repair after maturity; in severe deformities in children, two stages, with the rib cage corrected earlier [35]. The low agreement on recommendations R8.38 and R8.41 shows that the timing of thoracic surgery is the least consensual point among the experts. The Genoa experience explains the change in practice: thoracoplasty used to be proposed at 1–2 years, to protect the viscera when the child began to walk, but rib transfer gave poor results because the transferred rib tended to be resorbed, and absorbable meshes provided protection that disappeared with resorption; patients operated on early by the paediatric surgeon and later by the plastic surgeon were left with multiple scars, and the authors found no reports of visceral trauma in PS, so they abandoned early surgery [18]. The exception is respiratory failure: a newborn with agenesis of the 4th to the 9th ribs who could not be weaned from ventilation after repair of a coarctation of the aorta received absorbable prostheses in the first months, a tracheostomy and, at 1 year, titanium ribs, and was growing without further treatment at 4 years of follow-up [18].

7.5. Conservative treatment of the chest wall

In children with a compliant chest wall, the consensus regards the vacuum bell (negative-pressure suction cup for pectus excavatum), the FMF (Freire Martinez Ferro) orthosis and the compression brace for pectus carinatum as promising tools (R8.40, strong, 100%) [10]. In the Genoa adolescent series, 6 patients with carinatum used a compression brace and 2 with excavatum used a vacuum bell; 7 of the 8 moved down a TBN category (from T4 to T3 or from T2 to T1) and 4 did not need further rib surgery [16]. In 2018 the same group had begun to use dynamic compression or other braces in sternal rotation with contralateral carinatum and the vacuum bell in asymmetric depressions of the rib cage, only in pliable chests and as yet without publishable results [18].

7.6. Thoracic surgical techniques

Cardiac or pulmonary compression due to pectus excavatum is treated with a retrosternal metal bar by the minimally invasive Nuss technique (MIRPE, minimally invasive repair of pectus excavatum); an asymmetric anterior wall without compression is corrected by cartilage resection or osteotomy (sternochondroplasty) [10, 16]. In rib agenesis, surgery aims to protect the thoracic organs, abolish paradoxical breathing and stabilise the lung and rib cage [10]. The consensus uses an expanded polytetrafluoroethylene mesh (Gore-Tex) when one or two ribs are missing and a metal prosthesis from three ribs onwards, covered with Gore-Tex to prevent skin erosion; custom 3D-printed metal prostheses have been implanted in recent years (R8.45, strong, 100%) [10]. Correction of the severe thoracic anomaly should precede breast or pectoral reconstruction, or be performed simultaneously with the first plastic stage [10]. In Genoa, thoracoplasty with non-absorbable implants (Gore-Tex mesh and titanium bars) is performed from 13–14 years, in a multidisciplinary session: the paediatric surgeon stabilises the rib cage with bars between the agenesic ribs and the sternum, designed by 3D printing from the mirror image of the contralateral side, covers them with Gore-Tex and corrects at the same time the sternal rotation, carinatum or asymmetric cartilage prominence, and the plastic surgeon places the expander [18]. The authors applied the Nuss technique in 3 patients with PS, with one displaced bar that had to be repositioned; chest asymmetry is a risk factor for displacement and requires careful stabilisation, and the bar remains for 2 to 3 years, with plastic reconstruction able to begin at the same time as its removal, according to Tanner stage and psychological assessment. In association with the Currarino-Silverman sternal anomaly, correction is open, through a small transverse incision, with resection of the abnormal cartilages (usually two or three on each side), wedge sternal osteotomy if necessary, a Nuss bar if the lower part of the sternum compresses the heart and filling of a mild xiphoid depression with fragments of the removed cartilages [18]. Significant pectus, distinct from the frequent mild and asymptomatic forms, occurred in 25% of the series, and its surgical indications do not differ from those of patients without PS (symptoms and thoracic indices) [18].

In the Genoa series of 52 adolescents (2016–2023), thoracic surgery was indicated in 4 of 10 T2 patients, 1 of 2 T3 and 9 of 15 T4, and never in T1 [16]. Of the 17 patients with rib aplasia, 12 underwent thoracoplasty: Gore-Tex alone in 5 smaller defects, metal plates or bars in 3 and a custom titanium prosthesis in 4, always covered with Gore-Tex; 3 patients underwent MIRPE (two with two bars), with bar removal on average three years later, and sternochondroplasty, with resection of one to three cartilages, was performed in 13 or 14 patients (the text and the table of the article differ) [16]. Thoracoplasty and placement of the breast expander took place in the same session in 11 patients, and 90% were reclassified as T1 after thoracoplasty [16]. The rules proposed by the authors are: T1 never needs thoracoplasty; T2 and T3 may benefit; T4 requires thoracoplasty [16]. Translocation of contralateral ribs was abandoned because of donor-site injury [16]. Other techniques described are those of Ravitch, Nuss and Fonkalsrud, Marlex mesh with prosthesis and latissimus dorsi (Urschel), the methyl methacrylate prosthesis between two meshes (rigid and with a risk of infection), titanium bars with expanded polytetrafluoroethylene, the custom titanium implant after skeletal maturity and, in young children, the vertical expandable prosthetic titanium rib (VEPTR) [35].

7.7. Breast and pectoral reconstruction: principles and timing

Soft tissue reconstruction is mainly of aesthetic and quality-of-life value, and the pathway may begin at puberty, with TBN classification; plastic surgery consultations in the neonatal or prepubertal period serve to inform and reassure [10]. The plan should be as minimally invasive and debilitating as possible (R10.60, strong, 90%) [10]. In a study of 58 patients and 50 controls assessed with the Body Uneasiness Test, patients had more body uneasiness on all subscales; among those under 20 years, non-operated patients were the most affected, and operated patients had scores similar to those of controls, which led the authors to propose surgical planning during growth with minimally invasive techniques [55]. In the Genoa series, all girls were treated at Tanner stage IV and at least two years after menarche, and the authors regard adolescence as the preferred period, because body image and quality of life are better when reconstruction begins before 18 years [16]. Soft tissue reconstruction is not definitive, because the breast, muscle and fat change with age, pregnancy and habits, and the patient should be informed of the need for touch-ups throughout life (R14.85) [10].

Source: Italian consensus, Table 10 [10].

7.8. TBN algorithm of the Istituto Gaslini

The Genoa algorithm combines fat grafting, expanders and implants and excludes the latissimus dorsi [16]. In T1, B and N defects, it uses fat grafting, expanders and breast or pectoral implants, and in men a custom 3D-designed pectoral prosthesis; expanders and implants are placed subcutaneously, owing to the lack of pectoral muscle, and the expander is often placed in the superomedial quadrant, in an oblique position, to then move the NAC inferiorly [16]. All N2 patients needed an expander before definitive reconstruction; 37 of the 39 N2 patients became N1 without contralateral mastopexy, each keeping their own NAC [16]. The 2018 description explains the sequence: the first stage is usually an expander, because the subcutaneous tissue is scarce and the nipple is often displaced (N2, N3); in T1N1 patients expansion may be omitted and reconstruction is performed directly with an implant; in the others, expansion is slow, to avoid skin complications, and lasts at least 6 months, with fat grafting whenever possible; the last stage replaces the expander with a breast or pectoral implant, and fat grafting may be repeated. When adipose tissue is insufficient, particularly with total absence of the pectoralis major, an omental flap may be considered to cover the prosthesis and provide a more natural axillary fold. The authors recommend starting in early adolescence, so that body image stabilises along the pathway [18]. Fat grafting is used before, during and after the expander or implant, to improve skin trophism, volume, the axillary fold, residual defects, the implant profile and capsular contracture; in the three T1 boys in whom it was the sole technique, an average of two sessions was needed [16].

Source: Romanini 2024, Tables 5 and 6 [16].

With a mean follow-up of 5.9 years (3.3–7.6), there were five early complications (one post-thoracoplasty pneumothorax drained, two haematomas, one deep vein thrombosis and one dehiscence treated with negative-pressure therapy) and eight late complications (two capsular contractures, one symmastia and five subcutaneous oil cysts), with no major complications; mean satisfaction rose from 3.5 to 8.5 on a 1 to 10 scale [16]. The limitations are that postoperative assessment was only clinical and that satisfaction was measured with a simple scale [16]. The authors warn of iatrogenic symmastia in women [16].

The fat grafting technique described by the group is the «wet» technique, with infiltration of a modified Klein solution (1 mg of adrenaline, 10 mEq of sodium bicarbonate, 200 mg of mepivacaine hydrochloride and 50 mg of ropivacaine in 500 mL of 0.9% sodium chloride), manual harvesting with a 3 mm cannula 20 minutes later, gravity separation for 20 minutes and injection with 3 mL syringes; the donor sites are the abdomen and thighs, and the volume per session ranged from 30 to 240 mL [16]. This is a single-centre protocol and not a standard.

In 2026, the same group published a nipple-centred tissue expansion protocol, with anatomical expanders in customised positions, in 24 women operated on between 2012 and 2023: the sternal notch-to-nipple distance on the affected side increased from 16.04 ± 1.47 to 19.10 ± 1.32 cm, and the midsternal line-to-nipple distance from 8.77 ± 1.20 to 11.06 ± 0.98 cm; a higher BMI was associated with greater residual asymmetry, in an exploratory analysis [76].

7.9. Autologous flaps and divergence on the latissimus dorsi

The Salzburg group operated on 22 patients over 15 years of age (16 women; mean age at first surgery 28.1 years) between 2011 and 2020: microsurgical free flaps in 9 (deep inferior epigastric artery perforator, DIEP, in 3; transverse myocutaneous gracilis flap, TMG, in 6), pedicled latissimus dorsi in 2, implants in 9 and fat grafting alone in 2 men; 77.3% underwent at least one fat grafting procedure, with a mean of 1.7 sessions and a mean volume of 205 mL [51]. The overall complication rate was 45.5%, with five major complications: one breast haematoma, one donor-site haematoma, two flap necroses (both DIEP) and one cellulitis with abscess [51]. Among patients with previous implants, removal was due to capsular contracture in 6 of 9, rupture in 1 and dissatisfaction with shape in 2 [51]. The proposed algorithm differs by sex: in men, fat grafting for mild deformity and a myocutaneous flap (latissimus dorsi or TMG, the latter innervated as a functional substitute) for more pronounced forms; in women, implants with or without fat grafting for mild deformity and, in severe forms, DIEP if BMI is high or TMG in thin or athletic patients [51].

The latissimus dorsi is the point of greatest divergence between centres. The consensus restricts muscle transpositions to selected cases and to adulthood (R10.65–R10.66), and the Genoa group excludes the latissimus dorsi from its algorithm because it may be absent or hypoplastic in PS, does not correct skeletal defects, creates a muscle deficit in a healthy growing shoulder, does not replace the function of the pectoral muscle and may atrophy [10, 16]. Conversely, the Turkish series used latissimus dorsi transfer in 6 patients for symmetry and chest wall stabilisation, and the 2025 systematic review shows that flaps, mainly latissimus dorsi, were the most published technique (60.3% of cases) [15, 75]. In that review, expanders were used in 22.5% (all in women, 80.8% of them with a final implant), a flap alone was the most common option in men (41.7%) and the hybrid approach, flap with implant, in women (34.2%) [75]. Before proposing a latissimus dorsi transposition, its presence and function should be confirmed, because the muscle may be missing in PS [1, 10]. By 2018 the Genoa group had already abandoned the latissimus dorsi, until then regarded as the reference technique for reconstruction of the breast and axillary fold in PS, citing donor-site morbidity (shoulder weakness with functional limitation, secondary flap atrophy, poor aesthetic result) and the often insufficient development of the muscle in these patients [18].

7.10. Custom implants and implant surveillance

Custom silicone elastomer implants, computer-designed from CT, were used in an Irish centre in three patients between 2023 and 2024, with minimal morbidity and one repositioning [77]. The Salzburg group advises against combining the latissimus dorsi with custom implants in men, because of the need to replace the implants, approximately every decade, and capsular fibrosis [51]. Textured implants are associated with a risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), which justifies periodic clinical examination, as for capsular contracture [10]. Follow-up is annual after surgery with a breast or pectoral implant, with clinical examination and ultrasound (R14.84, strong, 100%) [10, 16]. Fat grafting does not interfere with breast ultrasound surveillance [35].

7.11. Rehabilitation

Source: Italian consensus, Table 11 (the original numbering does not include R11.71) [10].

Each intervention should be followed by a rehabilitation plan, and physiotherapy is indicated in complex cases [10]. The kinematic study of the shoulder, which showed posterior instability and altered scapular rhythm on the affected side, supports the assessment of scapular dynamics recommended by the consensus [52].

7.12. Psychological support

There is no specific literature on psychological support in PS, and the consensus recommendations are good practice [10]. Support begins with the parents, at the time of diagnosis, for bonding and parenting, and then moves on to the patient, for feelings of inadequacy and socialisation (R12.75–R12.76) [10]. Psychological assessment should precede any chest or breast reconstruction (R12.74), and in adolescents and adults it serves to ensure a self-determined decision, with realistic expectations, and not one taken solely on medical advice (R12.77–R12.78) [10]. The psychologist is a resource for the whole team, including in communicating the diagnosis (R12.79, strong) [10]. In the Italian survey, almost half of participants suffered consequences of diagnostic difficulties, 35.1% of a psychological nature [17]. In a 2026 British qualitative study of people who had been offered chest surgery, the dominant themes were self-esteem and body image, including gender pressures and lack of psychological support, the feeling of being «medically different» and treated as a case study, inconsistency of care over time and the prospect of «a lifetime of surgeries»; the authors call for an individualised pathway with psychological support [78].

7.13. Anaesthesia and the perioperative period

The 2020 consensus does not address anaesthesia, and the available information comes from a case report with literature review and a narrative review [28, 35]. Up to May 2017, the literature search found only four articles on anaesthesia in PS, with three patients aged between 8 months and 23 years [28]. The case described is that of a boy aged 5 years and 7 months, weighing 23 kg, with a right sternocostal cartilaginous defect of about 4 × 4 cm, absence of the pectoralis major and minor and the latissimus dorsi, paradoxical breathing only on deep inspiration and cardiac pulsation visible through the defect, who underwent thoracoscopy-assisted Nuss repair [28]. Anaesthesia was general, with total intravenous anaesthesia and pressure-controlled ventilation, and with ultrasound-guided bilateral thoracic paravertebral block at T4–T5 with ropivacaine; during passage of the introducer, severe ST-segment depression, a fall in end-tidal carbon dioxide from 34 to 28 mmHg and bradycardia from 110 to 40 beats per minute occurred due to cardiac compression, which reversed with withdrawal of the instrument, the Trendelenburg position, fluids and vasoactive drugs [28]. The article describes the block dose differently in the case report (ropivacaine 0.2%, 10 mL per side) and in the discussion (ropivacaine 0.25%, 0.5 mL/kg, with adrenaline 1:200,000), and these doses do not constitute a recommendation for PS [28].

The precautions proposed by these authors are: preoperative radiograph and CT; pulmonary function tests and blood gas analysis if there is restrictive or paradoxical breathing; echocardiogram, because of the possibility of dextrocardia; Doppler of the subclavian arteries and, if the vessel on the affected side is small or has low flow, blood pressure measurement and arterial line placement in the contralateral limb; central venous catheter and arterial line in Nuss repair, because the right hemithorax is smaller and the introducer enters from that side; controlled positive-pressure ventilation, because spontaneous breathing may worsen paradoxical breathing and lead to cardiopulmonary collapse; and regional analgesia preferred, given that the ipsilateral lung may be hypoplastic and predispose to postoperative respiratory depression [28, 35]. Thoracic epidural analgesia is used in Nuss repair, but vertebral anomalies may increase the risk; single-shot bilateral paravertebral block is the alternative described [28, 35].

Gui and colleagues, followed by a 2024 review, regard suxamethonium (suxamethonium) and inhalational anaesthetics as contraindicated in PS, because of the risk of malignant hyperthermia [28, 35]. This position rests on a 1999 letter on the risk of suxamethonium in children with musculoskeletal diseases and on a speculative overlap of chromosomal loci; the authors themselves acknowledge that there is no patient with PS in the literature who has had malignant hyperthermia [28]. It is a precaution by analogy, and not a documented risk. The situation is different when the differential diagnosis includes a congenital myopathy due to STAC3, in which susceptibility to malignant hyperthermia is genetic and documented [47]; in phenotypes with muscle or facial weakness, confirming the diagnosis before anaesthesia has practical consequences.

7.14. Pharmacological therapy and regulatory status

There are no drugs targeted at PS, nor have any marketing authorisation applications or opinions of the Committee for Medicinal Products for Human Use (CHMP) been found for this condition; a search of ClinicalTrials.gov in October 2026 identified no drug trials [79]. A negative search of that registry does not prove the absence of studies in other registries. The drugs used in patients with PS are those of anaesthesia, perioperative analgesia and surgical complications, at the usual doses for age and indication; there is no PS-specific dose to extrapolate.

Sources: ClinicalTrials.gov; Italian consensus; surgical series [10, 16, 77, 79].

7.15. Trials and intervention studies

The series are not comparable with each other: they differ in age (adolescents in Genoa, adults in Salzburg), severity, techniques and definition of complication, and none has a control group. The 45.5% complication rate in Salzburg includes microsurgical flaps in adults and cannot be compared directly with the absence of major complications in a paediatric series of expanders and implants. No negative trials have been published, and no suspended or withdrawn trials were found on ClinicalTrials.gov [79].

7.16. Developments in the last 12 months

Publications between the end of 2025 and October 2026 are observational (level IV) or case reports: the Genoa nipple-centred expansion protocol [76]; the Irish series of custom silicone implants [77]; the British qualitative study on the experience of chest surgery [78]; a case of transverse upper-limb deficiency that questions the single-point vascular hypothesis [38]; a diagnosis of PS at 62 years due to respiratory failure [56]; and a case of fetal detection through rib hypoplasia with diaphragmatic protrusion [57]. In 2025, the systematic review of reconstructive techniques, the kinematic study of the shoulder, the first case of thoracomelia and the association with atretic cephalocele were published [52–54, 75]. There was no update of the 2020 consensus up to October 2026 [10].

7.17. Pregnancy, lactation and transition

The sources consulted do not describe the course of pregnancy or breastfeeding in women with PS, including the lactation capacity of the hypoplastic breast. Pregnancy alters the volume and shape of the reconstructed breast, which may require subsequent corrections [10, 51]. Preservation of the contralateral breast, especially in young nulliparous women, is a consensus recommendation (R10.63) [10]. In women with extensive rib agenesis, respiratory function should be known before a pregnancy, in the light of the case of late respiratory failure described in 2026 [56]. Transition to adult care coincides with the reconstruction period: correction of recurrent syndactyly is performed in adolescence, chest reconstruction between 14 and 15 years and muscle transpositions only after complete psychophysical development, so the pathway should maintain continuity between paediatric and adult surgery [10]. The British qualitative study identified inconsistency of care over time as one of the main complaints [78].

7.18. Recommendations and divergences between sources

8. Reproductive Options and Family Counselling

8.1. Principles

Genetic counselling is recommended in all cases (R7.37, GCP, 100%) [10]. PS should be presented as a usually sporadic disorder, with exceptional familial recurrence, and counselling should be reassuring in families with one affected child and in affected adults without a family history (R7.33, strong, 100%) [10]. The information to be conveyed includes that the mechanisms are unknown, that most cases are isolated, that familial recurrence is below 10% and more frequent in males, and that non-recurrent genomic rearrangements have occasionally been associated [10]. In the 2018 Genoa series, among the 213 patients with family information, 89.2% were sporadic, 3.8% had another relative with PS and 7% had relatives with thoracic or upper-limb anomalies without complete PS; the authors advise informing that the risk of an affected person having a child with PS is higher than that of the general population and that, even in families with several affected members, the clinical presentation is variable and unpredictable, and they do not recommend routine karyotype or array-CGH, which they reserve for the most complex cases [18]. Communication should stress that PS is a non-progressive congenital anomaly, without disturbance of psychomotor development (R6.28), and that, without severe thoracic malformation, survival is comparable to that of the general population (R6.29) [10]. The diagnosis should be communicated to both parents, gradually and in an adapted manner, with a psychologist present or with a referral for external psychological support (R6.31), and with the contacts of surgeons and patient associations (R6.32) [10].

8.2. Examination of relatives

Before estimating the risk, parents and siblings should be examined to exclude undiagnosed mild forms, because intrafamilial expressivity is highly variable and some relatives have only symbrachydactyly, breast asymmetry or an isolated pectoral defect [9, 10, 14]. Pectoral ultrasound of the parents is useful when the clinical examination is equivocal; in the Genoa CNV series, parents with a suspected mild form had a normal ultrasound [7]. For detection of carriers in dominant conditions with incomplete penetrance, the Oxford Desk Reference recommends examining the hands and feet of the parents [33].

8.3. Recurrence risks by scenario

The risks of 25% and of up to 50% are those of the Mendelian models accepted by the consensus, and not frequencies observed in cohorts of families with PS [10]. In families with several affected members, the first step is to review the clinical diagnosis; if confirmed, specific Mendelian patterns or multifactorial inheritance are considered (R7.34, strong, 87.5%) [10].

8.4. Mosaicism and de novo cases

Sporadic cases may be partly explained by de novo events, and somatic mosaicism is one of the hypotheses that reconcile the asymmetry of the phenotype with a genetic cause [10]. The de novo 11q12.3 deletion in the Chilean monozygotic twins is the best documented example of a de novo genetic event associated with PS, but it does not define a recurrence risk applicable to other families [31]. None of the sources consulted describes proven germline mosaicism in PS.

8.5. Modifiable factors

Smoking during pregnancy was associated with an approximately twofold risk in two surveillance programmes, and stopping smoking is a general health recommendation that this finding reinforces [39]. The use of misoprostol, cocaine and other disruptive agents and invasive procedures in the first trimester are associated with vascular disruption defects, including those of the Möbius and oromandibular-limb spectra, and should be mentioned in preconception counselling [33, 40, 73].

8.6. Prenatal and preimplantation diagnosis

As there is no known gene, there is no prenatal or preimplantation molecular test for PS, and counselling is given without laboratory support (R7.35) [10]. The anomaly scan may detect forms with severe bony anomalies of the hands or rib cage, but misses most cases; when the parents are affected, the consensus does not recommend additional radiological investigations in utero (R3.12) [10]. The digits are rarely visualised clearly before 20 weeks [33]. Preimplantation diagnosis is applicable only when the family has an alternative diagnosis with an identified pathogenic variant. The Italian patient association offers preconception genetic consultation [22].

8.7. Counselling of minors and adults

Genetic testing of asymptomatic minors has no utility in PS, because there is no predictive test. In adolescence, information should also be directed to the patients themselves, who take part in decisions about surgery with psychological support (R12.77) [10]. An adult with isolated PS who asks about the risk to their children should be informed that, in the only population-based series that studied offspring, none of the 24 children of 8 affected adults had PS [13].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency estimates and what they measure

Frequency estimates for PS range from 1/7,000 to 1/100,000 births, and this range mainly reflects differences in definition, ascertainment method and severity of the cases included [17, 35, 51]. Studies with a described methodology are few and old.

Population-based registries mainly detect forms with a hand anomaly or chest deformity visible at birth; minimal forms, with a pectoral defect only, are often diagnosed in adolescence or adulthood and escape congenital anomaly registries, which leads the authors to regard the frequency as underestimated [17, 35]. A reference centre series cannot be used as an estimate of national prevalence, nor can the 1977 Canadian estimate be converted into a current prevalence for another population.

9.2. Sex and laterality

Male predominance is consistent: a ratio of 3:1 in textbooks, 27:17 in the Canadian series, 76:44 in the Italian CNV series and 2:1 to 3:1 in reviews [7, 13, 14, 31]. In the Italian survey of patients and carers, 56% of participants were female, probably owing to participation bias and the weight of breast asymmetry in care-seeking [17]. The right side predominates: 75% in textbooks, 59% in the series of 120 Italian patients, 55.7% in the Turkish series of 113 (with 7% bilateral) and 71% in the 2024 adolescent series [7, 14–16]. In families with true recurrence, the left side was more frequent (62.5%), with a male predominance of 87.5% [9].

9.3. Populations and regions

The largest clinical series come from Italy (Genoa and associated centres), Turkey, Canada and Austria, and data on families with recurrence and on CNV are almost exclusively Italian [7, 9, 13, 15, 51]. No founder populations are described, nor are differences in frequency between ethnic groups documented in the sources consulted. For the United States, the sources consulted do not include population-based frequency studies. For Portugal, the sources consulted provide no frequency data or clinical series. For Brazil, there is the clinical, genealogical and dermatoglyphic study by Freire-Maia and colleagues, published in 1973 and cited by the Italian series as a source of incidence estimates, whose figures were not read directly [7]. The Brazilian textbook of genetic syndromes documents Möbius sequence, with which PS overlaps, in the context of misoprostol use as an abortifacient, and gives a frequency for Möbius of 1/250,000 live births [73].

9.4. Population risk factors

Maternal smoking approximately doubled the risk in the Hungarian and Spanish programmes [39]. The mean paternal age of the British Columbia patients was higher than that of the population [13]. Limb reduction defects in general have a minimum prevalence of about 5.6/10,000 live births, are more frequent at the extremes of maternal age and fifteen times more frequent when there has been bleeding in the first trimester; in twins, the prevalence of limb anomalies is 40/10,000 and in triplets 60/10,000, figures that refer to limb defects as a whole and not to PS [33].

9.5. Special populations

In women, PS has specific consequences: breast asymmetry dominates care-seeking from puberty onwards, reconstructions have to keep pace with changes in pregnancy and weight, and the published breast cancer cases occurred on the affected side, with more difficult surgical and radiotherapy treatment [35, 51]. In men, the pectoral defect is the main aesthetic problem, and the options include fat grafting, custom pectoral prostheses and innervated muscle flaps [16, 51]. People diagnosed late, in adolescence or adulthood, benefit from psychodiagnostic assessment to exclude unrealistic expectations [10]. Access to care depends on distance from reference centres: in Italy, only Liguria and Lombardy had a specific diagnostic and therapeutic pathway at the time of the survey, and 88% of patients diagnosed outside their own region gave up consultations or treatments because of costs or organisational difficulties [17]. After the survey, reference centres were created in Apulia and Emilia-Romagna [17].

9.6. European reference networks and patient associations

The 2020 consensus was developed within ERN-BOND, the European reference network for rare bone diseases, and ERN ITHACA, the network for congenital malformations and rare intellectual disability, includes publications on PS [10, 21]. None of the sources consulted shows an official ERN disease list that expressly includes PS, so the two networks should be understood as those relevant for referral, and not as formal coverage. The Associazione Italiana Sindrome di Poland (AISP), founded in Genoa by parents and patients, promoted the consensus, maintains a patient registry described by the authors as the first PS registry, a reception and social counselling service and preconception genetic consultation, and is organising the «UNICInsieme» congress in Naples on 7 and 8 November 2026 (https://www.sindromedipoland.org/) [10, 22]. In the Italian survey, 91.2% of participants considered AISP useful [17]. In the United Kingdom, PIP-UK Poland Syndrome Support and Network, created in 2011 and inspired by the AISP model, provides individual support and programmes for adults and women (https://pip-uk.org) [23]; the British organisations Reach and STEPS support people with upper and lower limb differences [33]. The sources consulted do not identify specific associations in Portugal or Brazil.

10. Illustrative Clinical Case

10.1. Concordant monozygotic twins with a de novo 11q12.3 deletion

Vaccari and colleagues described in 2014 two monozygotic twin girls, daughters of healthy, non-consanguineous parents from Santiago, Chile [31]. There was no exposure to drugs, alcohol or infections during pregnancy, but the mother was admitted three times for threatened miscarriage. The twins were born at term, by spontaneous delivery, weighing 2.500 kg (5th centile) and 2.000 kg (below the 3rd centile), and measuring 45 cm and 40 cm in length; the second twin had severe birth asphyxia. Growth and psychomotor development were normal. According to the parents, the thoracic anomaly became clearly visible at around 10 years [31].

The first twin underwent surgery at 4 years for a thyroglossal duct cyst, a finding not previously described in PS, and had mild scoliosis at 12 years, without surgical indication. The second twin had severe congenital scoliosis due to a hemivertebra at T4 and butterfly vertebrae at T5–T6, operated on at 13 years. Both had a right-sided thoracic anomaly, with breast asymmetry, depression of the anterior wall due to pectoral hypoplasia, a cranially positioned nipple and a hypoplastic areola. The second twin also had mild hypoplasia of the right hand (16.8 cm, versus 17.7 cm on the left), without dysmorphic features; the hands of the first twin were symmetric. Echocardiogram and abdominal ultrasound were normal, and radiographs showed no other skeletal anomalies. The parents and the two siblings had no signs of PS on clinical examination [31].

At 17 years, both underwent surgical correction with a breast or pectoral implant chosen by measuring the contralateral side. At 19 years they measured 1.59 m and 1.53 m. Figure 1 of the article shows the chest of the two twins before surgery, with breast asymmetry, depression of the anterior wall, a cranial nipple and a hypoplastic areola on the right, and two years later, with mild asymmetry and pectoral hypoplasia still perceptible, more evident in the first twin (https://pmc.ncbi.nlm.nih.gov/articles/PMC4051386/figure/F1/) [31]. Figure 2 shows the hands at 19 years, without obvious anomalies, with the mild hypoplasia of the right hand of the second twin (https://pmc.ncbi.nlm.nih.gov/articles/PMC4051386/figure/F2/) [31].

Monozygosity was confirmed with nine microsatellite markers and amelogenin. A 180,000-probe array-CGH identified in both twins the heterozygous 126 kb deletion arr[hg19] 11q12.3(63,216,306-63,342,369)x1, absent in the parents and siblings, validated by quantitative PCR and by loss of heterozygosity, which showed the paternal origin of the deleted chromosome [31]. Sequencing of the five genes included showed no variants on the remaining allele [31].

The case illustrates several points of this article. The phenotype is that of the thoracic and breast form, with a minimal or absent hand defect, and was recognised in pre-adolescence, as happens with many forms without bony involvement of the hand. Concordance in monozygotic twins, with discordant severity (congenital scoliosis and hand hypoplasia in only one of them), is compatible both with a genetic contribution and with postzygotic or vascular factors. The de novo deletion is an observation that does not establish a PS gene, and the authors presented it as a hypothesis; a deletion of the same region was later found in another sporadic patient [7, 31]. The management, with cardiac and abdominal assessment, spinal surveillance and implant reconstruction at the end of adolescence, coincides with the recommendations of the consensus published in 2020 [10].

10.2. Complementary case: Poland–Möbius

Glass and colleagues described in 2022 a boy, the second child of first-cousin parents from Pakistan, born at term by elective caesarean section, without maternal exposure to medicines or drugs [5]. At birth he had right facial palsy, later also left, left symbrachydactyly, chest wall deformity and apparent absence of the left pectoralis major and NAC. Milk aspiration led to 20 days of admission to neonatal intensive care; the echocardiogram showed a patent ductus arteriosus and a moderate atrial septal defect, managed expectantly; he needed nasogastric tube feeding, had mild to moderate laryngomalacia and, because of persistent reflux and further aspiration, underwent gastrostomy with fundoplication. Brain MRI showed only a left frontal developmental venous anomaly, an incidental finding [5]. Before 12 months he had asymmetric bilateral facial palsies, bilateral failure of abduction, bilateral ptosis, complete absence of the left pectoralis major and NAC, hypoplasia of the left forearm and hand and symbrachydactyly with an acceptable thumb and thenar eminence and hypoplastic index, middle and ring fingers, with two phalanges and syndactylised [5]. The 1st and 4th web spaces were released at 18 months, and the child was considered a candidate for bilateral facial reanimation. Genetic testing found the PLXND1 variant NM_015103.3:c.2890G>A p.(Val964Met), inherited from the unaffected mother and classified as VUS [5, 44]. Figure 1 of the article shows the asymmetric bilateral facial palsy with convergent esotropia and ptosis, the absence of the left pectoralis major and NAC and the symbrachydactyly after web space release (https://pmc.ncbi.nlm.nih.gov/articles/PMC9801559/figure/Fig1/) [5]. The case shows how, in Poland–Möbius, feeding and the airway dominate the first year, and release of the 1st web space at 18 months was later than the 6–12 months that the consensus recommends when that web space is involved; the report does not explain the choice [5, 10].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

PS is a non-progressive congenital anomaly, and psychomotor development and growth are normal [10]. Without severe thoracic malformation, survival is comparable to that of the general population, and in most patients aesthetic problems are the only medical concern [3, 10, 14]. Major complications relate to the severity of the thoracic and upper-limb defects, and aesthetic problems may cause severe psychological distress in patients and parents, with an intensity that varies according to sex and educational level (R1.1–R1.2) [10]. Hand function depends on the Catena type: types I and II have no relevant limitation, and in types IV and V surgery and rehabilitation allow manual skills to be acquired, even with severe malformations [10]. The treated disease has good results in reference centre surgical series, with a downgrade of TBN category in all operated patients and an increase in satisfaction from 3.5 to 8.5 out of 10, but breast reconstruction requires touch-ups throughout life, and prostheses and implants are subject to capsular contracture and replacement [16, 51]. In forms with extensive rib agenesis and pulmonary hypoplasia, respiratory failure may develop in adulthood, as in the case diagnosed at 62 years [56]. In Poland–Möbius, the prognosis depends mainly on bulbar palsy and feeding difficulties [3, 5]. The oncological risk has not been quantified; the cases of breast cancer on the affected side justify attention, but do not support a screening protocol different from that of the general population [35].

11.2. Follow-up

Periodic follow-up looks for functional and aesthetic complications: limb anomalies, paradoxical chest wall movements, reduced lung function, muscle weakness and scoliosis [10]. Patients with upper-limb anomalies are followed by orthopaedics and hand surgery until the end of growth, because of the possibility of recurrence of syndactyly [10]. Genitourinary and cardiac malformations identified at the initial assessment are followed by the respective specialties [10].

The annual intervals apply only to surveillance after implants or fat grafting; for the other assessments, the consensus recommends periodic follow-up without setting the frequency, which should be adjusted to severity and growth [10].

12. Summary and Final Considerations

Poland syndrome, or sequence, is a unilateral congenital malformation defined by agenesis or hypoplasia of the pectoralis major, always with involvement of the sternocostal head, variably associated with hypoplasia of the breast, nipple and subcutaneous tissue, rib and sternal defects, Sprengel deformity and ipsilateral symbrachydactyly of the central rays [2, 10]. Birth frequency in population-based studies lies between 1/32,000 (Canada, 1970s) and 1.5/100,000 (Europe, 2005–2012), with male and right-side predominance, and minimal forms are underdiagnosed [1, 2, 13].

There is no established gene. Most cases are sporadic; 4.2% of families have recurrence of the pectoral defect and 8.4% have relatives with partial features, and the rare CNV found are heterogeneous and mostly inherited from healthy parents [7, 9]. The hypothesis of disruption of subclavian artery flow around the 6th week explains the association with Möbius, Klippel-Feil and transverse limb defects, but remains unproven, and is compatible with a genetic predisposition [10, 27]. In an atypical or complex phenotype, especially with muscle or facial weakness, alternative diagnoses with a known genetic cause should be considered, with consequences for recurrence risk and for anaesthesia [32, 46, 47].

The diagnosis is clinical and is confirmed by comparative musculoskeletal ultrasound; the initial assessment includes chest radiograph, echocardiography and abdominal ultrasound, and CT and MRI are reserved for surgical planning [10]. There is no routine molecular test or molecular prenatal diagnosis, and counselling is reassuring in isolated cases once the parents have been examined [10].

Treatment is surgical, rehabilitative and psychological, in a multidisciplinary pathway with defined time points: release of syndactylies between 6 and 24 months, conservative treatment of pectus in children, thoracic surgery from 12–13 years and breast or pectoral reconstruction from puberty onwards, with fat grafting, expanders and implants, and with muscle transpositions only in adulthood [10, 16]. The points of divergence between centres are the use of the latissimus dorsi, the relative role of ultrasound and CT and the timing of thoracic surgery [16, 35, 51]. The main gaps are the absence of recent population studies, including in Portugal and Brazil, the lack of quantification of the oncological risk and of renal anomalies, and surgical evidence limited to single-centre series [35, 75].

13. References

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