Ring Chromosome 15 Syndrome

Structural chromosomal anomaly in which a circular chromosome 15 replaces one of the homologues, with variable loss of terminal material from 15p and 15q (especially 15q26, where IGF1R lies) and the mitotic instability characteristic of ring chromosomes; growth restriction of prenatal onset, microcephaly, variable intellectual disability and pigmentary skin changes are the most constant features.

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Ring chromosomes as a class

The term "ring chromosome" describes the circular shape that the chromosome shows under light microscopy at metaphase. In its classic constitutional form, the ring replaces one of the two homologues and the karyotype is written 46,r(A), where A identifies the chromosome involved; small supernumerary rings, which are added to the two normal homologues, belong to another category, that of supernumerary marker chromosomes (SMC) [9, 20]. Orphanet groups these entities under ORPHA:363203 and maintains an entry for each autosomal ring, from r(1) to r(22), and for the sex chromosome rings [2, 30]. In international cytogenomic nomenclature, the abbreviation "r" designates a ring (for example, 46,X,r(X)) [31]; the current version is ISCN 2024 (An International System for Human Cytogenomic Nomenclature), which unifies the description of results obtained by karyotyping, FISH, microarray and sequencing and introduces for the first time a notation for genome mapping [32, 33].

The phenotype of any autosomal ring results from two overlapping components. The first is monosomy of the terminal segments lost when the ring forms, specific to each chromosome and each breakpoint. The second is common to all rings and has been called the "ring chromosome phenotype" (ring syndrome): instability of the ring during mitosis leads to loss, duplication or breakage of the ring in some cells, with cell death and growth restriction, even when the ring has lost no detectable material [20]. This second component explains why children with rings of different chromosomes share short stature, microcephaly, intellectual disability and pigmentary macules [20, 34].

1.2. Description of r(15) and historical milestones

The first description of a ring chromosome 15 is attributed to Jacobsen, in 1966 (indirect attribution, according to the review by Chen and colleagues) [10]. In 1985, Wilson and colleagues described a boy with prenatal and postnatal growth restriction, triangular face, fifth finger clinodactyly and limb disproportion, with r(15) in all leucocytes; their review of the cases then known delineated a malformation syndrome associated with loss of 15q26.2→qter and showed that microcephaly, intellectual disability, limb anomalies and heart disease were more marked in r(15) than in Silver-Russell syndrome (SRS), so the presence of these signs in a "Silver-Russell" phenotype justified a karyotype [35]. In 1988, Butler and colleagues described two patients and reviewed 25 cases, providing the first frequencies: growth retardation in 100%, intellectual disability of variable degree in 95%, microcephaly in 88% and delayed bone age in 75% [36].

The link to the insulin-like growth factor 1 receptor (IGF1R) emerged in the early 1990s. In 1991, Roback and colleagues mapped IGF1R distal to 15q26.1 from a child with a 15q26.1-qter deletion and monozygosity for the gene [11]. In 1993, Tamura and colleagues demonstrated by Southern blot and FISH the deletion of IGF1R in a girl with de novo r(15)(p12q26.3) and an SRS-like phenotype, which made it possible to assign the gene to 15q26.3 [37]. In 1995, Peoples and colleagues studied five patients with r(15): the three with severe growth retardation were hemizygous for IGF1R and the patient with borderline short stature retained two copies, establishing the correlation between gene dosage and growth [38]. In 1996, Rogan and colleagues, in a study with participation from Curitiba (Brazil), showed that patients with SRS were diploid for distal 15q markers, separating the two entities at the molecular level [39].

From 2004 onwards, FISH with BAC probes and, later, array comparative genomic hybridisation (aCGH) defined the breakpoints: Tümer and colleagues placed them in a 4.5–6.5 Mb window proximal to the 15q telomere in three patients, with IGF1R lost in all three and NR2F2 (COUP-TFII) included in the deletion of the case with heart disease [40]; Glass and colleagues showed, with aCGH, that two cytogenetically indistinguishable rings could differ in the extent of the deletion and that severity followed the size of the loss [41]. In 2017, Cannarella and colleagues documented in lymphocytes from a patient with r(15) a reduction in IGF1R messenger RNA and protein and the absence of receptor autophosphorylation after IGF-1 stimulation [13]. The 2018 to 2022 reviews brought together between 89 and 116 published cases [10, 21, 22].

1.3. Definition of the entities in this article

Ring chromosome 15 syndrome (r(15)). Constitutional chromosomal anomaly in which a ring chromosome 15 replaces one of the homologues, usually with loss of terminal material from 15q (breakpoints between 15q26.1 and 15qter) and from 15p; Orphanet defines it by the association of prenatal and/or postnatal growth retardation, variable intellectual disability, short stature, dysmorphism (microcephaly, triangular face, frontal bossing, hypertelorism, broad nasal root, high-arched palate, micrognathia, ear anomalies), anomalies of the hands and feet and multiple hyper- or hypopigmented macules, with heart disease and renal malformations in severe forms [1, 10].

15q26-qter deletion syndrome. Terminal monosomy of 15q without a ring, due to a simple deletion or unbalanced translocation. OMIM records it as a contiguous gene deletion syndrome (612626), with the alternative title Drayer syndrome, from two siblings described in 1977 in whom Rump and colleagues identified a 5.8 Mb deletion in 15q26.2-qter in 2008 [3]. Orphanet designates it "Distal deletion 15q syndrome" (ORPHA:1596) [4].

IGF-1 resistance due to an IGF1R defect. Intrauterine and postnatal growth restriction with microcephaly and normal or raised serum IGF-1, caused by heterozygous, homozygous or compound heterozygous IGF1R variants, or by intragenic or whole-gene deletions (OMIM 270450; ORPHA:73273) [5–7].

Small supernumerary ring marker chromosome 15 (sSMC r(15)). A small ring added to two normal chromosomes 15, usually derived from the pericentromeric region; the clinical risk depends on the presence of euchromatin from 15q11-q13 and on any associated UPD 15. It is an entity distinct from classic r(15) and is covered in the differential diagnosis [8, 9, 28].

2. Molecular Genetics and Pathophysiology

2.1. Formation of the ring

A ring chromosome forms by two mechanisms. In the more frequent one, breaks occur in the short and long arms and the broken ends of the segment containing the centromere join, with loss (monosomy) of the two terminal segments. In the second, the ends fuse at the level of the telomeres or subtelomeric regions, without loss of meaningful material, which allows a near-normal phenotype [20, 21]. In r(15), loss of 15p (an acrocentric short arm with ribosomal RNA genes repeated on other acrocentrics) has no known clinical consequence; the phenotype depends mainly on loss of terminal 15q [28]. The presence of a nucleolar organiser region (NOR) on the ring, demonstrated by silver staining in the case of Guilherme and colleagues, illustrates that the breakpoint in 15p can be very distal [24].

2.2. Mitotic instability and dynamic mosaicism

The ring replicates during interphase like any chromosome. Without sister chromatid exchange (SCE), the two daughter rings separate symmetrically. A single SCE creates a double dicentric ring which, pulled towards opposite poles at anaphase, may break; two SCE in the same direction produce interlocked rings, which also tend to break or fail to segregate; a second SCE in the opposite direction restores the initial situation [20]. The result is the appearance, at each division, of cells without the ring (monosomy 15, probably non-viable), with two rings, with a dicentric ring, with a broken or open ring, and of rings of different sizes between cells and between tissues, so-called dynamic mosaicism [20, 21]. The larger the ring, the greater the likelihood of mitotic disturbance [20]. The legend of the reference figure in the Oxford handbook mentions meiosis, but the text describes somatic division; the mechanism set out is mitotic.

The quantification by Guilherme and colleagues shows the order of magnitude of this phenomenon: in 300 lymphocyte metaphases from the same patient, cells with loss of the ring or with secondary aberrations (two monocentric rings, interlocked ring, dicentric ring, broken or open ring) accounted for 4.7% at 8 years and 7.7% at 28 years [24]. The prenatal karyotype of Glass and colleagues illustrates the same heterogeneity in a single sample: mos 46,XX,r(15)(p11.2q26)[32]/45,XX,−15[13]/47,XX,r(15)x2[3]/46,XX,dic r(15)[1]/46,XX[2] [41]. In the review by Chen and colleagues, 8 of 44 cases with cytogenetic data were mosaic for r(15); in the remainder, the ring was present in all cells analysed. Mosaicism r(15)/15qs+ and r(15) with an additional sSMC(15) have also been described, and the ring has been observed in amniocytes, chorionic villi, blood, bone marrow and skin [10]. Shao and colleagues described a mosaic with four cell lines, including rings composed of two chromosomes 15 (r(15;15)) and monosomy 15 [42].

Instability is considered the cause of the growth restriction common to all rings, independent of the genes lost, through cell loss and dysfunction of cell division [20, 24]. In r(15), this component adds to the haploinsufficiency of IGF1R [24].

2.3. The 15q26 region and the breakpoints

In 11 cases of r(15) studied by microarray (aCGH or single nucleotide polymorphism (SNP) microarray), the breakpoints lay between 15q26.1 and 15qter: eight terminal and three interstitial deletions, ranging in size from 500 kb to 8 Mb [10]. In the three patients of Tümer and colleagues, the breakpoints clustered 4.5–6.5 Mb proximal to the 15q telomere [40]. Rogan and colleagues identified at least three distinct breakage sites near the telomere and a ring with a terminal and an interstitial deletion on the same chromosome [39]. In 15q26-qter deletion without a ring, the siblings with Drayer syndrome had a recurrent 5.8 Mb deletion in 15q26.2-qter, with a proximal breakpoint at 94.52 Mb [3].

The published cases have allowed critical regions to be proposed. Hatem and colleagues, from a fetus with intrauterine growth restriction (IUGR) and congenital diaphragmatic hernia (CDH), placed the critical region for CDH in 15q26.1-q26.2 and that for IUGR in 15q26.3 [43]; the review by Traisrisilp and colleagues takes up the CDH region in 15q26.1-q26.2, usually lost in r(15) [44].

2.4. IGF1R: structure, function and mechanism

IGF1R (OMIM 147370; HGNC:5465; 15q26.3) has 21 exons [11]; the ClinGen GRCh38 coordinates (chr15:98,648,539–98,964,530) span about 316 kb, a value consistent with the size of 315,991 bp given by Cannarella and colleagues and larger than the estimate of about 100 kb published in 1992 [11–13]. The MANE Select reference transcript is NM_000875.5 (protein NP_000866.1) [12, 45]. The gene encodes a 1367-amino-acid precursor with a 30-residue signal peptide; cleavage of the proreceptor generates the α subunits (extracellular, ligand binding) and β subunits (transmembrane, with a tyrosine kinase domain), similar to the insulin receptor [11]. The receptor binds IGF-1 with high affinity and IGF-2 and insulin with lower affinity; binding triggers autophosphorylation and phosphorylation of the substrates IRS1 and IRS2, activating the PI3K-AKT and RAS-MAPK pathways, which regulate prenatal and postnatal growth, protein synthesis and cell survival [7]. In juvenile human tissues, IGF1R expression is biallelic, unlike what has been described in the mouse, in which Igf1r and Igf2r are imprinted; the parental origin of the lost allele should therefore not alter the effect of haploinsufficiency [11]. In the mouse, homozygous inactivation of Igf1r reduces birth size to about 45% of normal and is lethal through respiratory failure [11].

The resulting deficiency is one of signalling, not of ligand: the child has cellular resistance to IGF-1, not a lack of IGF-1. The mechanisms described include haploinsufficiency, reduced receptor biosynthesis, interference with ligand binding or transmembrane signalling, and loss of tyrosine kinase activity [7, 46]. Attenuation of negative feedback on the somatotrophic axis tends to raise circulating IGF-1 above the mean for age, the mirror image of primary IGF-1 deficiency [7]. ClinGen classifies IGF1R as having sufficient evidence of haploinsufficiency (score 3) and no evidence of triplosensitivity (0), with loss-of-function intolerance metrics pLI 1 and LOEUF 0.39 [12]. IGF1R deletions have not been observed in healthy individuals [10].

Functional proof in r(15) comes from two studies. De Lacerda and colleagues, in Curitiba, demonstrated in a girl with r(15) a 50% reduction in IGF1R DNA and messenger RNA, binding of labelled IGF-1 to fibroblasts of 0.69% compared with 1.41% in the control, and in vivo resistance to short-term administration of recombinant IGF-1 [47]. Cannarella and colleagues observed, in lymphocytes from a patient with 46,XX,r(15)(p10q26.2), IGF1R messenger RNA less than half that of the control, reduced protein content and undetectable receptor autophosphorylation after 10 nM IGF-1; the authors acknowledge the limitation of having used a 17-year-old male control [13].

The dosage effect works in both directions. Distal duplication of 15q (15q25/26-qter) causes the so-called 15q overgrowth syndrome, although overgrowth occurs in 42–53% of the patients reviewed and IUGR or growth retardation in 12–25%, which shows that three copies of IGF1R are not sufficient for overgrowth [13, 48]. Nagai and colleagues described, in a family with a t(13;15) translocation, postnatal overgrowth in trisomy 15q and IUGR in monosomy 15q (indirect attribution, according to the Oxford handbook) [49].

The oncological literature on IGF1R refers to somatic overexpression in tumours, where the receptor is an anti-apoptotic factor and a therapeutic target; a germline loss of function in a child with short stature is a growth disorder and does not imply tumour predisposition [7].

2.5. Other 15q26 genes and proposed correlations

This table must be interpreted with caution. Not all patients with height below −3 standard deviations (SD) have an IGF1R deletion [10], and there are rings with growth restriction without loss of the gene: Szabó and colleagues described an r(15) with a 1 Mb deletion in 15q26.3 that spared IGF1R, associated with an sSMC(15) with a 2.6 Mb gain in 15q11.2, in a child with severe growth retardation [50]; in the Iranian family of Kalantari and colleagues, the 563 kb deletion in 15q26.3 did not include IGF1R and the carriers had short stature [18]. These cases support a contribution from the ring itself (mitotic instability) or from the region distal to IGF1R. At the opposite extreme, Shao and colleagues described a ring without a detectable deletion and with a 2.0 Mb microduplication in 15q26.3 (CHSY1, ALDH1A3, LRRK1, LINS1) in a woman with a mild phenotype diagnosed because of infertility [42].

The OMIM data on the candidate genes make it possible to separate what is plausible through a dosage effect from what would only be so through unmasking of a recessive allele. For NR2F2, Al Turki and colleagues identified eight heterozygous variants in ten patients with diverse congenital heart defects (atrioventricular septal defect, tetralogy of Fallot, aortic stenosis with VSD, hypoplastic left heart syndrome and coarctation of the aorta), including a de novo balanced translocation with a breakpoint in the first intron, predicted to be a null allele; in two families, the variant was inherited from an unaffected parent, indicating incomplete penetrance [14]. NR2F2 variants have also been described in a child with ASD and left CDH and in patients with isolated CDH, and the conditional knockout mouse develops posterolateral Bochdalek-type diaphragmatic hernias, similar to those of patients with a 5 Mb deletion in 15q26.1-q26.2 [14]. Frameshift variants of NR2F2 were identified in three 46,XX children with genital virilisation and congenital heart disease, and Carvalheira and colleagues described a 20-year-old 46,XX man with ovotesticular difference of sex development (DSD), coarctation of the aorta and blepharophimosis-ptosis-epicanthus inversus syndrome, carrying a de novo 3 Mb deletion in 15q26.2 that includes NR2F2 and SPATA8 [14]. The sources consulted do not describe DSD in patients with r(15). For MEF2A, the 21 bp deletion described in a family with dominantly transmitted coronary artery disease was later found in controls, without cosegregation with early coronary disease in the respective families, and Biggio and colleagues proposed the gene as a candidate for CDH because of the frequency of 15q24-q26 anomalies in this malformation [15]. CHSY1 and LINS1 are associated with recessive disorders (Temtamy syndrome and intellectual developmental disorder 27, both described in consanguineous families), so deletion of one allele would only have a predictable clinical consequence if the remaining allele carried a pathogenic variant [16, 17].

2.6. Genotype–phenotype correlations and modifiers

The series do not agree on the relationship between deletion size and severity. Glass and colleagues associated severity with the size of the loss (about 6 Mb in the severe case; only one subtelomeric and one interstitial clone lost in a 31-year-old woman living independently) [41], and Peoples and colleagues associated severe growth retardation with hemizygosity for IGF1R [38]; Rogan and colleagues found no correlation between the severity of growth retardation and the size of the deleted interval [39]. In the series of Chen and colleagues, patients with deletions of similar size but with ring mosaicism had more marked dysmorphism and skeletal anomalies than a non-mosaic patient, and the authors propose the degree of mosaicism, ring instability (additional gains and losses) and parental origin as modifiers [10]. Other variables cited are loss of euchromatin from 15p and/or 15q, tissue mosaicism and a possible position effect due to circularisation, the latter a hypothesis [24]. In mosaics with a normal cell line (ring of postzygotic origin), a different proportion of abnormal cells in each half of the body may produce asymmetry, and mosaic pigmentary macules are a marker of this phenomenon [20, 28].

Chromosome 15 contains the imprinted region 15q11-q13. Classic r(15) retains this region and the phenotype does not depend on the parental origin of the ring in most cases; Unique states that the ring derives with equal probability from the paternal or maternal chromosome 15 [28]. Rogan and colleagues associated, in several patients, the parental origin of the ring with Prader-Willi or Angelman features and proposed as an explanation postzygotic loss of the ring with UPD of the intact chromosome 15 in some tissues (hypothesis) [39]; Tümer and colleagues described a patient with features similar to those of Prader-Willi syndrome [40]. In the study by Cannarella and colleagues, the absence of paternal alleles in the deleted region and the authors' conclusion that the rearrangement would not be of paternal origin are contradictory statements, so the parental origin of that ring cannot be deduced from the publication [13].

2.7. IGF1R variants and nomenclature

The molecular spectrum of IGF-1 resistance includes missense, nonsense and splicing variants, intragenic deletions and whole-gene deletions, the latter generally part of a terminal 15q26 deletion [5, 7]. Heterozygotes generally have a milder phenotype than the rare compound heterozygotes or homozygotes [5, 7]. The smallest intragenic deletion published up to 2010 spanned exons 11 to 21 (95 kb) and segregated with short stature in seven members of a three-generation Dutch family, with normal IGF-1 and no consistent sign of peripheral resistance [3].

The numbering of the historical OMIM variants is not uniform: some use the numbering of the mature protein (without the 30-amino-acid signal peptide) and others that of the precursor. The following table presents only conversions validated in VariantValidator on the MANE transcript; variants whose c. notation is not published in the source consulted keep their historical designation, without conversion.

The genomic coordinates of the deletions in the r(15) cases were published in old assemblies (hg18 in Guilherme 2012; hg19 in Shao 2020; assembly not stated in Paz-y-Miño 2018) and are not converted here to GRCh38 [21, 24, 42].

2.8. Allelic disorders and related entities

Four situations with clinical overlap derive from the same locus: r(15) with loss of IGF1R; pure terminal 15q26-qter deletion, with an overlapping growth phenotype [3, 10]; IGF-1 resistance due to point variants or intragenic deletions, without the ring instability component and generally without the neighbouring genes [5]; and distal duplication of 15q, with overgrowth in some patients [13]. Bloom syndrome, caused by biallelic BLM variants (OMIM 604610), lies in the same region (15q26.1) but is an autosomal recessive DNA repair disorder, with no mechanistic relationship to the ring [53, 54].

3. Clinical Spectrum and Manifestations by System

3.1. Sources of the frequencies and their limitations

There are no population cohorts of r(15). Clinical frequencies come from reviews of published cases, subject to publication bias (severe or unusual cases), incomplete data per patient and variable denominators. The three main reviews measure different things: Butler and colleagues (1988) reviewed 25 cases [36]; Paz-y-Miño and colleagues (2018) gathered 97 cases published since 1966 plus their own case, but always divided by 98, counting cases without information as absent, which underestimates the frequencies [21]; Chen and colleagues (2021) identified 116 cases published up to March 2021, analysed 78 with usable data plus their own case and calculated each frequency over the patients with information available for that item [10]. The guide from the Unique association adds data from member families (surveys from 2004 and 2017), without fixed denominators [28].

Sources: [10, 21, 36]. CNS, central nervous system; ASD, atrial septal defect; VSD, ventricular septal defect.

The three data sets converge on a core formed by growth restriction of prenatal onset, microcephaly and intellectual disability or developmental delay; Paz-y-Miño and colleagues consider that no common phenotype has been established beyond these features with a frequency above 40% [21]. In the review by Chen and colleagues, the mean age at postnatal diagnosis was 9.7 years and there were 40 females to 24 males, a female predominance with no known explanation [10].

3.2. Growth

Growth restriction begins in the fetal period. In the cases reviewed by Paz-y-Miño and colleagues, mean birth weight and length were 2252 g and 43.94 cm in girls and 2345 g and 46.29 cm in boys [21]; in 12 babies from Unique families, birth weight ranged from 1.1 to 2.8 kg (mean 2.1 kg, including three preterm infants) [28]. Postnatal growth remains below the mean, without catch-up, with a proportionate body; Unique reports a birth length of about 48 cm and an expected adult height of about 152 cm in most, with predicted extremes between 91 and 137 cm [28]. In the published adults not treated with growth hormone (GH), final height lay between −6.8 and −2.5 SD, and the Brazilian patient followed for 20 years by Guilherme and colleagues reached 146.5 cm (−2.6 SD) [10, 24]. Bone age is delayed in most cases assessed [10]. Unique records the case of an adolescent who almost stopped growing for six months without GH [28].

The growth component of r(15) overlaps with that of IGF1R haploinsufficiency, which on its own produces a typical height of −2.5 to −3 SD with delayed bone age [55], and with the non-specific ring component [20]. Serum IGF-1 in the published patients with r(15) lies within the reference interval or above the mean: 448 ng/mL (reference 143–693) at 11.5 years in the case of Chen and colleagues and 186 ng/mL (reference 87.4–399.3) at 11 years in the case of Cannarella and colleagues [10, 13].

3.3. Skull and face

Microcephaly is the sign that most clearly separates r(15) from SRS, in which head circumference (HC) is relatively preserved [56, 57]. The facial features described include triangular face, micrognathia or retrognathia, broad nasal root, high-arched palate, low-set or dysplastic ears, hypertelorism, downturned corners of the mouth, strabismus, epicanthus, short palpebral fissures, short philtrum, frontal bossing and sparse temporal hair [10, 21]. With age, the facial features tend to become less marked [24]. Trigonocephaly and craniosynostosis requiring craniotomy in a Unique member, and hypoplasia of the corpus callosum, have been described [28].

3.4. Development, cognition and behaviour

Intellectual disability is generally mild to moderate in r(15), which differs from the general description of autosomal rings in the Oxford handbook (moderate to severe) [20, 28]. In the Butler series, children sat on average at 11 months and walked at 22 months; in Unique families they sat at 10 months (5–18) and walked at 23 months (10 months to 3 years). Hypotonia affects about a quarter [28]. First words appeared on average at 20 months in six children in the Butler series; all Unique families report speech and language difficulties, with comprehension better than expression, and sign language is useful [28]. In learning, memory is often good and abstraction and mathematics more difficult; most attend mainstream school with support [28]. Paz-y-Miño and colleagues describe an infant with normal psychomotor development at 15 months, which shows that delay is not universal [21].

The behaviour described is sociable and cooperative, with over-familiarity with strangers, tantrums and stubbornness; there are isolated cases of attention-deficit/hyperactivity disorder (ADHD), depression and obsessive-compulsive disorder in one adult [28]. The patient of Guilherme and colleagues developed compulsive eating in adulthood and aggression when thwarted [24]. In the Fryns series, cited by Guilherme and colleagues, the marked verbal difficulties between 4 and 6 years later disappeared and attention deficit with hyperactivity regressed before 7 years (indirect attribution) [24]. Sleep problems (mild apnoea, awakenings) are frequent at some point and improve with age [28].

Seizures are infrequent: two Unique members (focal seizures treated with phenobarbital, seizure-free after 2 years; absences) and one adult with suspected seizures [28]; Chen's review includes seizures in the group of CNS abnormalities [10].

3.5. Skin and adnexa

Café-au-lait macules (33.8% in Chen's review) and hypo- or hyperpigmented macules (15.6%) are characteristic findings [10]. The Oxford handbook states that the café-au-lait macules associated with ring chromosomes are indistinguishable from those of neurofibromatosis type 1 [34]. Boente and colleagues described in two girls with r(15) small café-au-lait macules paired with hypopigmented macules (didymosis, twin spotting), a picture called cutis tricolor parvimaculata [58]; Ribeiro Dias Barroso and colleagues described the same picture in a 2-year-old girl [59]. Unique attributes the macules to ring mosaicism and cites a girl with a very distal breakpoint, with no functional genes lost, who had macules and premature greying (Morava 2003, indirect attribution) [28]. In adults, hirsutism, dry skin, fine hair and acanthosis nigricans have been described [24].

3.6. Skeleton, hands and feet

Skeletal deformities affect about half of the patients with data: clinodactyly (27.1%), brachydactyly (22.9%), small hands and feet (20.3%), talipes equinovarus (11.4%) and kyphosis (8.6%) [10]. Other findings are brachymesophalangy, hypoplastic proximally placed thumbs, syndactyly, arachnodactyly, scoliosis, hip dysplasia, joint hypermobility, patellar dislocation and elbow synostosis [21, 24, 28]. The patient of Cannarella and colleagues had a supernumerary phalanx in the third finger of both hands and hypoplasia of the phalanges of the second and third fingers [13]. Alhashem and colleagues described 11 pairs of ribs and crossed fused renal ectopia [22].

3.7. Heart

Congenital heart disease occurs in 20.8% in Chen's review and in one third to one fifth in the series cited by Unique [10, 28]. The defects described include ASD, VSD, patent ductus arteriosus, pulmonary stenosis, hypoplasia of the aorta, mitral atresia or hypoplasia, atrial hypoplasia and dilated cardiomyopathy [10, 21]. Postnatal junctional ectopic tachycardia has been described in one child and bradycardia in one adult [28]. The relationship with loss of NR2F2 is not constant [10]; loss-of-function variants of this gene cause congenital heart defects with incomplete penetrance, which is consistent with that inconsistency [14].

3.8. Urogenital system, puberty and fertility

Urogenital anomalies (33.3%) include cryptorchidism, hypogenitalism, phimosis, hypospadias, uterine hypoplasia, renal hypoplasia and polycystic kidneys [10]. In the Butler series, cryptorchidism affected about one third of boys and hypospadias about one fifth [28]. Renal anomalies affect up to one fifth (mild hydronephrosis, small functioning kidney) [28]. In men, oligozoospermia, asthenozoospermia and azoospermia are frequent and most are infertile; in women, sexual development and gonadal function are generally normal, with uterine hypoplasia described in some [10, 24]. Puberty is usually normal (menarche at about 12 years in two Unique girls; regular menstruation from 14 years in Guilherme's patient), with one man with incomplete puberty [24, 28]. The case of Chen and colleagues began central puberty at 11.5 years and had a mesosalpinx cyst, the first description of this association [10].

3.9. Eyes, hearing and teeth

About three quarters of Unique members have visual problems: strabismus (often surgically corrected), high myopia, astigmatism and macular abnormalities [28]. Puchalska-Niedbał and colleagues treated a 60 prism dioptre exotropia with amblyopia conservatively, obtaining a residual deviation of 10 dioptres, visual acuity of 1.0 in both eyes and normal binocular vision [60]. About one third have hearing loss, mainly conductive [28]. Dental anomalies include delayed eruption, fragile enamel, crowding, bruxism and ectopic teeth in the palate [21, 28].

3.10. Feeding and digestive system

All Unique families report early feeding difficulties (weak suck, high palate in about one fifth, gastro-oesophageal reflux, occasional fundoplication or gastrostomy) and reduced appetite, which are overcome with time [28]. Hirschsprung disease and severe chronic constipation have been described in isolated cases [28]. In adulthood, overweight occurs in some patients (9.2% in the Paz-y-Miño review; central obesity and a body mass index of 27.23 kg/m² at 27 years in Guilherme's patient) [21, 24].

3.11. Prenatal manifestations

In the seven fetuses with r(15) published up to January 2022 with ultrasound data, the findings were fetal growth restriction (FGR) in 5/6 (83.3%), CDH in 4/6 (66.7%), thickened nuchal fold in 4/7 (57.1%), abnormal limb postures in 3/6, low-set ears in 3/6, oligohydramnios in 2/5 and congenital heart disease in 2/5 [44]. These cases represent severe forms and do not reflect the fetuses with normal ultrasound who are born and diagnosed later; most survivors had no prenatal diagnosis [44]. In the pregnancies of 11 Unique families, four were uneventful, six had a small fetus, three oligohydramnios, one polyhydramnios and three ended in preterm delivery at about seven months [28].

3.12. Related entities: 15q26-qter deletion and IGF1R defects

Pure terminal deletion of 15q has the same growth phenotype as r(15) [10]. Orphanet describes prenatal and postnatal growth restriction, developmental delay, variable intellectual disability, anomalies of the hands and feet (brachydactyly, clinodactyly, talipes equinovarus, nail hypoplasia, proximally placed digits) and mild craniofacial dysmorphism, with neonatal lymphoedema, heart disease, aplasia cutis congenita, aortic root dilatation and autism spectrum disorder described [4]. In Drayer syndrome, the two siblings had microcephaly, moderate to severe intellectual disability, blepharophimosis, hearing loss, ASD and absent middle phalanges of the second and fifth fingers [3]. The international guideline on SGA children adds CDH, hearing loss and pulmonary hypoplasia [3, 25].

In IGF1R defects due to a point variant or small deletion, the constant triad is IUGR, postnatal growth without catch-up and microcephaly, with IGF-1 above the mean for age [7, 46]. In the Leiden series (Walenkamp and colleagues, 2019; 18 patients with variants and 7 with 15q deletions including IGF1R), mean birth weight, length and HC were −2.1, −2.7 and −1.6 SD; at presentation, height was −3.0 SD, HC −2.5 SD and IGF-1 +1.2 SD; 15 of 19 had feeding problems [61]. IGF-1 may be low in the first years because of feeding difficulties [7]. Developmental delay is variable and not universal; the first patients described were the most severe [7]. The SGA guideline estimates that heterozygous IGF1R variants or deletions account for 1–2% of SGA children with short stature, with birth weight between −3.5 and −1.5 SD and length between −5.0 and +0.3 SD [25]. In a survey of adult carriers (Göpel and colleagues, 2020), no excess comorbidity was detected compared with adults born SGA, with small numbers [7, 62]. In the biallelic cases in OMIM, insulin-dependent diabetes in adolescence, hyperinsulinism and a progeroid phenotype occur [5].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

The Oxford handbook describes three routes of ascertainment of ring chromosomes: investigation of a child with developmental delay, dysmorphism and/or poor growth, which is the most frequent; a fetal anomaly; and an incidental finding at amniocentesis or chorionic villus sampling [20]. For r(15) in particular, the situations in which it should be suspected are as follows.

4.2. Warning signs

The association of short stature of prenatal onset with microcephaly is the main warning sign. Wilson and colleagues already recommended karyotyping when microcephaly, intellectual disability, dysmorphism, limb anomalies or heart disease accompany a picture suggestive of SRS [35], and the review by Fokstuen and Kotzot shows that r(15) and 15qter deletion lack relative macrocephaly and have more severe intellectual disability than SRS [56]. The 2023 SGA guideline states that IGF-1 values repeatedly above +1 SD in a child with microcephaly require IGF1R testing and that a high IGF-1 with a low GH dose during treatment should prompt consideration of such testing [25]. Mosaic pigmentary macules or body asymmetry suggest chromosomal mosaicism and justify studying another tissue if blood is normal [20, 66].

4.3. Urgent situations

In the newborn, CDH with pulmonary hypoplasia is the manifestation with the greatest immediate risk: in the case of Britto and colleagues, the child was born at 36 weeks weighing 1430 g and died at 2 hours from respiratory failure [64]. Complex congenital heart defects (hypoplasia of the aorta, coarctation) require neonatal cardiological assessment [3, 44]. Severe feeding difficulties may justify tube feeding or gastrostomy [28]. In 15q26 deletion, recurrent hypoglycaemia has been described in one child [3]. In children on GH, hip or knee pain with limping, persistent headache with visual disturbance and progression of scoliosis are warning signs described in the labels [67].

4.4. Newborn screening

There is no newborn screening for r(15) or for IGF1R defects.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic definition

There are no formal clinical criteria for r(15). The diagnosis is cytogenetic: demonstration of a ring chromosome 15 replacing one of the homologues, with characterisation of the lost material by microarray or an equivalent technique [10, 20]. Because the common phenotype is non-specific, diagnosis is late (mean age 9.7 years in published postnatal cases) [10].

5.2. Cytogenetic and genomic tests

Chromosomal microarray. The consensus of the ISCA (International Standard Cytogenomic Array) consortium, based on 33 studies with 21,698 patients, showed a diagnostic yield of 15–20% for chromosomal microarray in patients with developmental delay, intellectual disability, autism spectrum disorder or multiple congenital anomalies, compared with about 3% for karyotyping, and recommended it as a first-tier test; the same consensus acknowledges that balanced rearrangements and low-level mosaicism are generally not detected [23]. In the context of rings, the clue on microarray is loss of material from the ends of both arms of the same chromosome; in r(15), loss of 15p is not visible on most platforms (acrocentric arm), so the usual finding is a terminal 15q26 deletion [10, 20]. In the SGA guideline, microarray identifies a pathogenic copy number variant (CNV) in about 15% of SGA children with short stature and an unrecognised syndrome [25]. SNP microarrays are more sensitive than oligonucleotide arrays for estimating the mosaic fraction [66].

Conventional karyotype. Microarray shows the deletion but does not show the ring; G-banded karyotyping is required to demonstrate the ring structure, to document dynamic mosaicism and for counselling [20, 23, 24]. In the patient of Guilherme and colleagues, the SNP microarray did not detect the dynamic mosaicism visible on the karyotype [24]. The Oxford handbook recommends counting 30 cells to look for mosaicism (30 cells without mosaicism exclude 10% mosaicism with 95% confidence) and asking the cytogenetics laboratory for an annotated photograph of the ring, useful in counselling [20, 66]. The same handbook notes, in relation to rings 14 and 20, that mosaic rings are better detected by karyotyping [68].

FISH and other techniques. FISH with 15q subtelomeric probes and with IGF1R probes confirms the deletion and the presence of the ring; it was the technique that enabled the first prenatal diagnosis with characterisation of the terminal deletion [37, 63]. Multiplex ligation-dependent probe amplification (MLPA) detects whole-gene or intragenic IGF1R deletions [3, 69, 70]. Exome sequencing with CNV analysis detected the 4.5 Mb deletion in the case of Chen and colleagues, confirmed by quantitative PCR [10].

Alternative tissues. If suspicion of mosaicism persists with normal lymphocyte microarray and karyotype, another tissue should be studied (fibroblasts from a skin biopsy, saliva, FISH on a buccal smear) and the laboratory informed, because the microarray software may not flag mosaicism [66].

Parental study. Karyotyping and microarray of the parents, with a 30-cell count for mosaicism, are recommended to distinguish a de novo ring from an inherited ring [20].

5.3. Nomenclature of the result

The result follows ISCN 2024 [32, 33]. Two published examples show the combined karyotype and microarray notation, 46,XX,r(15)(p13q26.2)dn.arr 15q26.2q26.3(94,810,000-100,338,900)×1, with coordinates in hg18 [24], and the notation of a dynamic mosaic, mos 46,XX,r(15)(p11.2q26)[32]/45,XX,−15[13]/47,XX,r(15)x2[3]/46,XX,dic r(15)[1]/46,XX[2] [41].

The report should state the genome assembly, the coordinates of the deletion, the copy number, the genes lost (in particular IGF1R and NR2F2), the estimate of mosaicism and the number of cells analysed on karyotyping. For IGF1R sequence variants, the report should contain the gene, the versioned transcript (NM_000875.5), the HGVS c. and p. notation, the zygosity and the class according to the ACMG/AMP (American College of Medical Genetics and Genomics / Association for Molecular Pathology) criteria [12, 45]. IGF1R variants of uncertain significance (VUS) require segregation studies with phenotype (parental height and HC) and, when available, functional studies in fibroblasts, as in the OMIM cases [5].

5.4. Endocrine and IGF axis assessment

Assessment of the somatotrophic axis includes serial measurements of height, weight, growth velocity and HC; IGF-1 and IGF-binding protein 3 (IGFBP-3) expressed as SD for age; a GH stimulation test when deficiency is suspected; assessment of glucose–insulin homeostasis (fasting glucose and insulin with the homeostasis model assessment index, HOMA, or an oral glucose tolerance test, OGTT) and bone age [7]. The SGA guideline recommends thyroid hormones and IGF-1 (± IGFBP-3) and reserves the GH test for suspected deficiency [25]. In r(15), the published GH peaks range from low values (4.69 ng/mL with levodopa in Chen's case) to normal values (up to 35.6 ng/mL with clonidine) [10]; an isolated low peak should not be interpreted as deficiency without confirmation, because IGF-1 is usually normal or high [10, 61].

An IGF-1 above the mean or raised in a child with IUGR, without postnatal catch-up and with microcephaly points towards IGF-1 resistance, but no IGF-1 value distinguishes an IGF1R defect from other causes of resistance; confirmation requires copy number analysis and sequencing [7]. The clinical score of Walenkamp and colleagues (birth weight and length, short stature, microcephaly and IGF-1) had a sensitivity of 76% for selecting patients for IGF1R testing [61].

5.5. Limitations of the tests

A negative result in a single tissue does not exclude mosaicism. A 15q26 deletion on microarray does not distinguish r(15) from a simple terminal deletion or an unbalanced translocation; only karyotyping, possibly with FISH, makes this distinction, which has consequences for the recurrence risk [20, 69].

5.6. Prenatal diagnosis

r(15) can be identified in amniocytes, chorionic villi and fetal blood [10, 44]. In the seven fetuses published up to 2022, the mean gestational age at ultrasound diagnosis was 17.4 ± 8.7 weeks and maternal age 30.9 ± 3.0 years [44]. There are no specific maternal serum markers and early ultrasound may be normal [44]; in the case of Manolakos and colleagues, the 11-week scan was normal and autopsy showed CDH, polycystic kidneys and limb anomalies [44]. Three-dimensional ultrasound in rendering mode helps to assess low-set ears and a depressed nasal root [64]. Liu and colleagues made the first prenatal diagnosis (nuchal fold of 8 mm and IUGR at 20 weeks; amniocentesis 46,XY,r(15); telomeric FISH with terminal deletion of 15q) [63]. In the fetus of Traisrisilp and colleagues, cordocentesis showed 45,XX,del(15)[4]/46,XX,r(15)[26] [44]. Prenatally, mosaicism for a ring or marker requires specific interpretation, because villus mosaicism may not represent the fetus [71].

5.7. Practical algorithm

6. Differential Diagnosis

6.1. Differential diagnosis table

6.2. Silver-Russell syndrome

SRS is the main clinical differential diagnosis and the one most often confused with r(15): both have growth restriction of prenatal onset, triangular face, fifth finger clinodactyly and café-au-lait macules [35, 37]. SRS presents with birth length and weight near −2 SD, minimal postnatal catch-up, preserved HC with relative macrocephaly, late closure of the anterior fontanelle, body asymmetry, downturned corners of the mouth, excessive sweating, fasting hypoglycaemia between 10 months and 2–3 years, feeding difficulties in 86% and learning difficulties in about one third [57]; mean untreated adult height is about −4 SD [25]. Loss of methylation of ICR1 at 11p15 accounts for 38–64% of cases and maternal UPD 7 for 5–10% [56]; OMIM also records forms caused by variants of IGF2, PLAG1 and HMGA2 [73]. Rogan and colleagues showed that patients with SRS are diploid for distal 15q [39].

The first international consensus (2017) defined SRS clinically, by the Netchine-Harbison clinical scoring system (NH-CSS), and accepted that a normal molecular result did not exclude it [79]. The second consensus, published online on 23 September 2026 (with an authors' correction on 30 September) and developed through a Delphi-type process, makes the diagnosis molecular: SRS is defined by loss of methylation at 11p15 H19/IGF2:IG-DMR (through an imprinting defect, CNV or upd(11)mat) or by upd(7)mat (recommendation 1.1), and the threshold for molecular testing should be lower below 2 years, in adolescence and in adulthood, because of a lack of auxological data (recommendation 1.3) [72]. An NH-CSS ≥ 4 occurs in 96% of patients with 11p15 loss of methylation and in 93% of patients with upd(7)mat, but has low specificity; the term "suspected SRS" is reserved for those who have, at about 2 years, an NH-CSS ≥ 4 with relative macrocephaly in the first 28 days and a prominent forehead, a negative comprehensive molecular work-up and discussion with a clinician experienced in the syndrome (recommendation 2.1) [72]. The first-line molecular test is methylation analysis of H19/IGF2:IG-DMR and KCNQ1OT1:TSS-DMR (11p15), of GRB10:alt-TSS-DMR and MEST:alt-TSS-DMR (chromosome 7) and of MEG3:TSS-DMR (14q32), which also diagnoses Temple syndrome; only after these changes have been excluded is testing for SNV, CNV and UPD proposed, including at least IGF2, CDKN1C, HMGA2 and PLAG1 (recommendations 4.3–4.8), and a negative report should state that it excludes neither SRS nor mosaicism (recommendation 4.9) [72]. The consensus considers PLAG1 and HMGA2 variants distinct entities, as they are not consistently associated with relative macrocephaly, and does not include IGF2 or CDKN1C in the molecular definition because of a lack of phenotypic data [72]. Among the clues to an alternative diagnosis, it lists head circumference below −2 SD (IGF1R variant or deletion, PLAG1, HMGA2, upd(20)mat, chromosomal instability disorders), height of a parent below −2 SD, consanguinity, global developmental delay or intellectual disability (CNV) and photosensitive facial erythema (Bloom syndrome); in chromosomal instability disorders such as Bloom syndrome, GH should only be used with caution, after discussion with the haemato-oncology team and with close follow-up (recommendation 3.1 and supporting text) [72]. For r(15), the consequence is that a patient with an SRS-like phenotype and r(15) should be identified by the chromosomal aberration and not labelled as SRS, a conclusion already put forward by Fokstuen and Kotzot when reviewing chromosomal aberrations with an SRS phenotype (11p15 duplications, 12q14 deletions, r(15), 15qter deletion and others), which lack relative macrocephaly and have more marked intellectual disability [56, 72]. The consensus does not refer specifically to ring chromosomes; according to its own clues, microcephaly and developmental delay, which are frequent in r(15), point towards karyotyping and microarray alongside methylation testing [72].

6.3. Terminal 15q26 deletion without a ring

The difference between r(15) and a simple terminal deletion is cytogenetic and not clinical: the growth phenotype is the same, and the OMIM synopsis and the review by Cannarella and colleagues describe short stature, low birth weight, microcephaly, psychomotor delay, micrognathia, triangular face, low-set ears, strabismus, blepharophimosis, broad nasal root, septal heart defects, hypospadias, cryptorchidism, micropenis, brachydactyly, absent or hypoplastic middle phalanges and talipes equinovarus [3, 13]. Guilherme and colleagues counted about 12 pure distal 15q26 deletions published up to 2012, with CDH, complex heart defects, renal anomalies and pulmonary hypoplasia among the findings [24]. The Oxford handbook states that no submicroscopic 15q deletions have been described [49]; this statement has been superseded by the 15q26 microdeletion including IGF1R of Rudaks and colleagues (2011) and by the 95 kb intragenic deletion in the family of Veenma and colleagues (2010) [3, 80]. The distinction has two practical consequences: the deletion may result from an unbalanced translocation, as in the Turkish patient of Çelik and colleagues with a 3.3 Mb 15q26.3 deletion and a 2.6 Mb 9p24.3p24.2 duplication [69], which requires the parents to be studied; and there is no mitotic instability.

6.4. IGF-1 resistance due to IGF1R variants

Patients with IGF1R point variants share the growth triad of r(15) but generally without the malformations associated with the neighbouring genes and without the ring component [7, 46]. OMIM documents dominant inheritance with maternal transmission (mother and children with IUGR and short stature) and recessive inheritance in consanguineous families, with more severe phenotypes (VSD, progeroid phenotype, diabetes) [5]. The Leiden series, which brought together 18 patients with variants and 7 with deletions, showed similar phenotypes in the two groups [61].

6.5. Small supernumerary chromosomes 15 and UPD 15

SMC are found in about 3 per 1000 children investigated for developmental delay, compared with 0.5 per 1000 live births; about 70% derive from acrocentrics, and those derived from chromosome 15 (idic(15)/inv dup(15)) are among the most frequent [9]. The phenotype depends on whether the marker contains the Prader-Willi/Angelman critical region (SNRPN probe): chromosome 15 markers without that region are almost always associated with a normal phenotype, and when the marker contains euchromatin from an imprinted region, UPD should be studied in the proband and the parents [9]. Unique distinguishes the supernumerary ring 15 from classic r(15) and states that mosaics with a supernumerary ring and UPD may give Prader-Willi (maternal UPD) or Angelman (paternal UPD) pictures [28]. Lee Curtis and colleagues described a maternally derived sSMC ring 15 associated with mosaic paternal UPD 15, probably through trisomy rescue, which made a pathogenic SLC12A1 variant homozygous and caused Bartter syndrome type 1 [8]. idic(15) has a birth prevalence of 1–9/100,000 according to Orphanet and presents with central hypotonia, global delay, intellectual disability, autism spectrum disorder and seizures [76].

6.6. Bloom syndrome

The BLM gene lies at 15q26.1, but Bloom syndrome is an autosomal recessive chromosomal instability disorder due to a defect of a RecQ helicase, with prenatal growth deficiency (mean birth length 43.4–43.8 cm and weight 1.87–1.89 kg; mean adult height 148.5 cm in men and 141.5 cm in women), mild microcephaly with dolichocephaly, photosensitive telangiectatic facial erythema, hyper- and hypopigmented areas, immunodeficiency, diabetes and risk of neoplasia (20% according to the Oxford handbook) [53, 54, 74, 75]. The differential is relevant because the SGA guideline advises against GH in disorders with a high cancer predisposition, such as chromosomal instability syndromes and DNA repair defects [25].

6.7. The class of ring chromosomes: classification and table of types

The class is organised according to three criteria. The first is the relationship with the chromosome complement: rings that replace a homologue (46,r) and small supernumerary rings, the latter classified as SMC [9, 20]. The second is the chromosome of origin, which defines the Orphanet entries (ORPHA:363203 and sub-entries by chromosome) [2, 30]. The third is the content of the ring: loss of terminal segments (monosomy phenotype added to the ring phenotype) or telomeric fusion without loss (isolated or absent ring phenotype) [20, 21]. X rings are further divided into large rings (Turner variant, with 45,X or 46,XX mosaicism) and small rings without XIST (functional X disomy, intellectual disability that may be severe) [20]. The class as a whole has a birth prevalence of 1–9/100,000 (mean 2.0/100,000) according to Orphanet, which cites Jacobs and colleagues (1975); the abstract of this reproductive fitness study does not present that estimate [2, 81]. Rings in general account for 0.5% of the rearrangements causing cri du chat syndrome [82].

The following table summarises the Orphanet definitions for each ring. The "cases" column gives literature counts cited by Orphanet, not prevalence; for almost all, prevalence is below 1/1,000,000 or unknown. None of these rings has a phenotypic OMIM entry of its own in the sources consulted.

Table source, unless otherwise stated: [30]. The common features (growth restriction, microcephaly, café-au-lait macules, intellectual disability) reflect the ring component; the distinguishing features (cataract in r(16), lissencephaly in r(17), epilepsy in r(20), GH deficiency in r(18)) reflect the genes lost.

7. Treatments and Risk Management Strategies

7.1. General principles

There is no treatment directed at the cause of r(15) and no specific guideline for the condition. Management is multidisciplinary and rests on three pillars: treatment of the growth deficit, mainly with GH; detection and treatment of malformations and complications (cardiac, renal, auditory, visual, orthopaedic, dental); and support for development and learning [10, 28]. The Oxford handbook recommends, for any ring, consulting the gene map of the lost regions to identify disease genes that justify specific surveillance, such as tumour suppressor genes or dominant disease genes [20]; in r(15), the lost genes of established clinical interest are IGF1R and, in larger deletions, NR2F2 [12, 40].

7.2. Growth hormone (somatropin)

Rationale and framework. Recombinant GH is the only pharmacological therapy studied in r(15) [10, 86]. r(15) is not an approved indication; treatment is given under the indication for children born SGA without catch-up growth, meeting the criteria for that indication, or off-label when they are not met [7, 25]. The 2023 international SGA guideline (ten paediatric endocrinology societies, including the European Society for Paediatric Endocrinology, ESPE, and the Pediatric Endocrine Society, PES) is the reference for the dose; it applies to r(15) by extrapolation, because r(15) shares growth restriction of prenatal onset and IGF1R haploinsufficiency, one of the genetic defects that the guideline itself lists among the causes of SGA [25]. Many national authorisations exclude children with features suggestive of a dysmorphic syndrome (with the exception of SRS), so the eligibility of a child with r(15) is decided case by case [25].

Results in r(15) and in IGF1R defects. The review by Chen and colleagues brought together ten patients with r(15) treated with GH (two with combined therapy, with a gonadotrophin-releasing hormone analogue, GnRHa, or oxandrolone): start at 6.5 ± 3.9 years, duration 1.8 ± 1.4 years, and, in the six with data, height of −4.9 ± 1.1 SD before and −3.8 ± 0.6 SD after, a gain of +1.1 ± 0.9 SD (p < 0.05), without complete catch-up [10]. The systematic review by Wannes and colleagues (13 patients, including a new case treated with a high dose) found a median gain of +1 SD (0.3–1.8) over 1.7 years and an increase in growth velocity of 4.1 cm/year [86]. In the British series of Ho and colleagues (seven children with 15q26 deletion including IGF1R, three of them with r(15)), the median gain was +0.6 SD at the first year (n = 7), +1.3 SD at 5 years (n = 4) and +1.4 SD at 10 years (n = 3); four reached final height with a median change of +1.1 SD (0 to +3.3) [87]. The three patients with r(15) in this series had gains of +0.5 to +1.0 SD in the first year and two reached final heights of −2.1 and −2.5 SD after 12 years of treatment [69]. Glass and colleagues described a good response in the first year and stagnation in the second [10]; Nuutinen and colleagues, an increase from −6.2 to −4.4 SD over two years [88]; and Tümer and colleagues, a treated boy measuring 164 cm at 18 years (−1.4 SD) [10].

In IGF1R defects in general, Çelik and colleagues reviewed 28 treated patients: a gain of at least 0.5 SD in the first year occurred in 61% of terminal deletions or r(15) and in 35% of point variants, and a gain of at least 1 SD at the last assessment in 69% and 42%, respectively; 46% of those who did not gain 0.5 SD in the first year reached 1 SD with prolonged treatment [69]. In the Leiden series, GH at a dose of 1.1 mg/m²/day for three years gave gains of +0.9 SD with variants (n = 12) and +1.3 SD with deletions (n = 7), with a mean IGF-1 of +3.5 SD, above that observed in treated SGA children (+1.8 SD) [61]. In the comparison by Göpel and colleagues (23 carriers of IGF1R variants vs 34 SGA children), the first-year gain was 0.29 vs 0.65 SD and the proportion of poor responders 53% vs 17%; good responders with a variant reached levels comparable to those of SGA children [62]. Insulin resistance, equal before treatment, was greater in variant carriers during GH [62]. There are favourable individual results with early initiation, such as the girl with a 15q26.2→qter deletion treated from 5 years who reached normal adult height [70] and the Portuguese child with biallelic variants treated from 13 months [51].

Reference dose (guideline). In children born SGA, the guideline recommends doses between 0.033 and 0.067 mg/kg/day (the upper limit, 0.067 mg/kg/day, is the maximum of the recommended range), starting at 0.033 mg/kg/day (equivalent to about 1 mg/m²/day); the dose is increased within the range if the height gain in the first year is less than 0.5 SD, and a higher starting dose may be considered in the most affected children; treatment should not be started at 0.067 mg/kg/day, because that dose raises IGF-1 to near or above +2 SD without additional adult height gain; IGF-1 should be kept up to +2 SD and the dose is not titrated on IGF-1 alone [25]. Administration is subcutaneous and daily, divided into 6–7 weekly injections in the labels [89, 90]. The literature on IGF1R diverges on dose: Çelik and colleagues, citing Leal and colleagues, advocate higher than usual doses to overcome receptor resistance, whereas Göpel and colleagues found no association between dose and response [62, 69]. Because IGF-1 is usually raised in these patients, the +2 SD limit is reached with lower doses; the guideline notes that a high IGF-1 with a low dose should prompt a search for an IGF1R defect or a syndrome with tumour predisposition, such as Bloom or Fanconi syndromes, and a discussion of treatment with the parents [25].

Doses in the labels (comparison). The labels approved by the US Food and Drug Administration (FDA) and the summaries of product characteristics (SmPC) approved by the European Medicines Agency (EMA) and by INFARMED (the Portuguese National Authority of Medicines and Health Products) differ from the guideline on two points: the minimum age and the way the dose is expressed.

The European and Portuguese SmPCs also require discontinuation after the first year if growth velocity is below +1 SD and discontinuation when velocity is below 2 cm/year and bone age is above 14 years in girls or 16 years in boys [92, 93]. The guideline recommends stopping when velocity is below 1 cm in 6 months with closed epiphyses, or in the event of non-adherence or repeated lack of response [25]. Göpel and colleagues recommend critical and periodic reassessment of the benefit of treatment in carriers of IGF1R defects [62]. In the European SGA trials of Omnitrope®, doses of 0.033 and 0.067 mg/kg/day until final height gave gains of +1.90 and +2.19 SD in 56 patients with final or near-final height [92].

Regulatory criteria for the SGA indication. According to the guideline's comparative table, the minimum starting age is 2 years in the USA and Latin America, 3 years in Japan and 4 years in Europe; the height threshold is −2.0 SD in the USA and Latin America and −2.5 SD in Europe and Japan; Europe and Japan require a growth velocity below 0 SD and Europe a distance from target height greater than 1 SD; the FDA label sets no SD threshold [25].

Presentations. In Portugal, the SmPC consulted is that of Genotropin® 5.3 mg/1 ml and 12 mg/1 ml, powder and solvent for solution for injection (somatropin; first authorisation in 1992) [93]. In Brazil, according to the open data of the National Health Surveillance Agency (ANVISA), several somatropins are registered (Genotropin®, Norditropin®, Omnitrope®, Saizen®, Biomatrop®, Criscy®, Eutropin®, Hormotrop® and the Bio-Manguinhos somatropin), as well as somapacitan (Sogroya®) and somatrogon (Genryzon®); the indications approved in Brazil are not included in the open data consulted [94].

Contraindications, adverse effects and management. The Genotropin® label contraindicates GH in acute critical illness after open-heart or abdominal surgery, multiple trauma or acute respiratory failure, in Prader-Willi syndrome with severe obesity or severe respiratory impairment, in active neoplasia, in hypersensitivity, in proliferative or severe non-proliferative diabetic retinopathy and with closed epiphyses [67]. Warnings include second neoplasia in cancer survivors, glucose intolerance and diabetes (monitor blood glucose), intracranial hypertension (exclude papilloedema), fluid retention, hypoadrenalism, hypothyroidism (monitor thyroid function), slipped capital femoral epiphysis (assess limping or hip or knee pain), progression of scoliosis and pancreatitis [67]. In the European SmPC, effects related to fluid retention (peripheral oedema, arthralgia) are very common and musculoskeletal stiffness, myalgia and paraesthesia common, generally mild, in the first months, and they regress spontaneously or with dose reduction; about 1% of patients form antibodies without clinical consequence [92]. In the SGA child, the SmPC requires fasting insulin and glucose before treatment and annually, an OGTT if there is a risk of diabetes (family history, obesity, severe insulin resistance, acanthosis nigricans), no administration in overt diabetes, IGF-1 before treatment and twice a year, no initiation near the onset of puberty, and mentions limited experience in SRS [92, 93]. The SGA guideline records that GH lowers free thyroxine in 14% of children through increased conversion to triiodothyronine, without thyroid dysfunction, and reduces insulin sensitivity without type 2 diabetes in long-term studies; the SAGhE project showed no overall increase in cancer in treated SGA children, and a Swedish cohort found a hazard ratio for cardiovascular events of 1.97 (95% confidence interval, 95% CI, 1.28–3.04), with a low absolute risk [25]. In carriers of IGF1R defects, the increase in insulin resistance during GH justifies specific glucometabolic surveillance [7, 62]. In a boy with an IGF1R deletion treated with GH, partial hypogonadotrophic hypogonadism, central hypothyroidism and borderline central adrenal insufficiency occurred; the authors recommend monitoring puberty and thyroid function in these patients [69].

7.3. Long-acting growth hormone

Somapacitan (Sogroya®, Novo Nordisk) is a GH derivative administered weekly. On 27 February 2026, the FDA approved extension of the indication to children from 2.5 years with short stature born SGA without catch-up by 2 years, to Noonan syndrome and to idiopathic short stature, at a dose of 0.24 mg/kg/week (actual body weight) subcutaneously (0.16 mg/kg/week in GH deficiency), individualised according to growth response and with no paediatric maximum dose defined in the label (the maximum of 8 mg/week refers to adults with GH deficiency) [95]. The supporting phase 3, open-label, randomised, active-comparator trial (NCT05330325) included 142 prepubertal SGA children (2.6–10.7 years; mean baseline height −3 SD); at week 52, annualised height velocity was 11.0 cm/year with somapacitan (n = 70), 9.4 cm/year with somatropin 0.035 mg/kg/day (n = 37) and 11.1 cm/year with somatropin 0.067 mg/kg/day (n = 35); the difference vs 0.035 mg/kg/day was +1.6 cm/year (95% CI 0.91–2.23) and vs 0.067 mg/kg/day −0.1 cm/year (95% CI −0.75 to 0.60) [95]. The most frequent adverse reactions in the SGA cohort were nasopharyngitis (26% with somapacitan), respiratory infections (26%), pyrexia (19%), cough (16%), otitis (13%), diarrhoea and vomiting (10% each); there was one case of adenotonsillar hypertrophy treated surgically [95].

In the European Union, Sogroya® has been authorised since 31 March 2021 for paediatric GH deficiency from 3 years and for adult GH deficiency. On 17 September 2026, after re-examination of an initial opinion from May 2026, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for three new paediatric indications: SGA (with the same height, velocity and age-4 criteria as the somatropins), Noonan syndrome and idiopathic short stature, the latter only after re-examination. The European Commission decision was pending at the date of consultation, so the SGA indication is not yet authorised in the EU [96]. In Portugal, Infomed lists Sogroya® as authorised and marketed in pre-filled pens of 5 mg/1.5 ml, 10 mg/1.5 ml and 15 mg/1.5 ml [97]. The current SmPC, under centralised authorisation (first authorisation on 31 March 2021), keeps paediatric GH deficiency from 3 years and adult GH deficiency as indications; in children, the starting dose is 0.16 mg/kg/week subcutaneously, titrated by IGF-1 sampled 4 days after injection (target between −2 and +2 SD, preferably close to 0; if the value remains above +2 SD on a second measurement, reduction by 0.04 mg/kg/week; subsequent increases of at most 0.02 mg/kg/week up to 0.16 mg/kg/week), with assessment every 6–12 months and discontinuation when growth velocity is below 2 cm/year and bone age is above 14 years in girls or 16 years in boys [98]. The SGA dose of 0.24 mg/kg/week in the FDA label is 50% higher than the paediatric maximum of the European SmPC, which refers to GH deficiency; there is not yet an approved European dose for SGA [95, 98]. Somatrogon (Ngenla®) is approved in the USA only for paediatric GH deficiency from 3 years [99]. There are no data on these medicines in r(15) or in IGF1R defects; their use in these situations would be an extrapolation of the SGA indication (in the USA) or off-label (in the EU) [95, 96].

7.4. Gonadotrophin-releasing hormone analogues

The SGA guideline recommends adding two years of GnRHa to GH when predicted adult height at the onset of puberty is below −2.5 SD, with a mean adult height gain of 6.6 cm [25]. This is an off-label use, as the label indications refer to central precocious puberty. In r(15), Chen and colleagues combined triptorelin 3.75 mg intramuscularly every 28 days (four doses) with GH in a girl with central puberty at 11.5 years [10]; in the Dutch family with an intragenic IGF1R deletion, combined treatment with GH and luteinising hormone-releasing hormone from 14 years allowed catch-up of 32.3 cm over 4.6 years [3]. Among the formulations with an FDA paediatric label, prolonged-release triptorelin (Triptodur®) is given as a 22.5 mg intramuscular injection every 24 weeks from 2 years, with monitoring of luteinising hormone or sex steroids 1–2 months after starting and of height every 3–6 months [100]; leuprorelin (Lupron Depot-Ped®) is used as a monthly dose of 7.5 mg (up to 25 kg), 11.25 mg (more than 25 to 37.5 kg) or 15 mg (more than 37.5 kg), or as 3-monthly (11.25 or 30 mg) and 6-monthly (45 mg) formulations [101]. The triptorelin dose used in Chen's case corresponds to the monthly 3.75 mg formulation; there is no specific guideline dose for delaying puberty in SGA children.

In Portugal, triptorelin is authorised and marketed as Decapeptyl® 3.75 mg (monthly administration), Decapeptyl® LP 11.25 mg (3-monthly) and Decapeptyl® LP 22.5 mg (6-monthly), all indicated for central precocious puberty starting before 8 years in girls and 10 years in boys [102–104]. In central precocious puberty, the SmPCs provide for Decapeptyl® 3.75 mg intramuscularly every 28 days with a weight-adjusted dose (half the reconstituted volume below 20 kg, two thirds between 20 and 30 kg and the full dose above 30 kg), Decapeptyl® LP 11.25 mg intramuscularly every 3 months and Decapeptyl® LP 22.5 mg intramuscularly every 6 months (24 weeks) from 2 years; the subcutaneous route has not been studied in children, and treatment should stop at around the physiological age of puberty, not continuing in girls with bone maturation above 12–13 years and with discontinuation advised in boys with bone maturation of 13–14 years [102–104]. The dose of 3.75 mg every 28 days used in the case of Chen and colleagues matches the full dose that the Portuguese SmPC provides for children over 30 kg. Delaying puberty that has started at a normal age in an SGA child or a child with r(15) is outside the indications of these SmPCs, which are limited to central precocious puberty; the reference for this use is the recommendation of the SGA guideline [25, 102].

7.5. Recombinant IGF-1 (mecasermin): an agent to avoid

Mecasermin (Increlex®) is approved by the FDA for severe primary IGF-1 deficiency (height ≤ −3.0 SD and basal IGF-1 ≤ −3.0 SD with normal or raised GH) and for GH gene deletion with neutralising antibodies, from 2 years, and the label states that it is not a substitute for GH in GH indications [105]. The label dose is 0.04–0.08 mg/kg twice daily subcutaneously, which may be increased by 0.04 mg/kg per dose up to a maximum of 0.12 mg/kg twice daily, given close to a meal because of the risk of severe hypoglycaemia [105]. The 2016 PES guideline limits the use of recombinant IGF-1 to primary IGF-1 deficiency [77]. Children with r(15) or IGF1R defects have normal or raised IGF-1 and do not meet this definition; supplying more ligand does not compensate for a deficient receptor [7, 61]. The only published use in r(15) is the physiological study of De Lacerda and colleagues, with 40, 60 and 80 µg/kg twice daily for 2–2.5 days at each dose, which showed unchanged urinary nitrogen excretion, a 60% increase in urinary calcium and non-significant suppression of GH, that is, in vivo resistance [47]. Mecasermin has no therapeutic role in r(15).

7.6. Non-pharmacological and surgical interventions

All Unique members with information received physiotherapy, started between birth and 12 months, with reported benefit for rolling, sitting and walking; most received occupational therapy from 4 months (coordination, hand use, oral stimulation) and speech therapy from about 1 year until school age, and sign language was useful during language acquisition [28]. Strabismus was surgically corrected in most Unique members with strabismus [28]; Puchalska-Niedbał and colleagues showed that conservative treatment (refractive and prismatic correction, occlusion and orthoptic exercises, from 15 months to 8 years) can correct a large exotropia with amblyopia [60]. Conductive hearing loss was treated with ventilation tubes in two members and with middle ear reconstruction in one adult; hip dysplasia with a harness in two cases and surgery in one; feeding difficulties with tube feeding, gastrostomy or fundoplication in selected cases; and craniosynostosis with craniotomy [28]. Heart defects follow the usual treatment for each lesion: in the case of Chen and colleagues, the VSD detected at 7 months was closed at 6 years [10]. School support and curricular adaptations allow most to attend mainstream school [28]. In counselling and treatment decisions for people with learning difficulties, the Oxford handbook recommends ample consultation time and appropriate consent for each intervention [20].

7.7. Comparative regulatory status

7.8. Trials and treatment series

Treatment data in r(15) come exclusively from case reports and small retrospective series, without a control group or randomisation, with heterogeneous doses, ages at start and durations, and with publication bias in favour of favourable responses. The existing controlled trials were conducted in SGA children without an identified syndrome, and their application to r(15) is an extrapolation; there is no direct comparison between somapacitan and daily somatropin in r(15), and results from different trials are not comparable with each other. The IGF1R data include an unfavourable result (Göpel: three times as many poor responders as SGA children) that limits the expected gain. A ClinicalTrials.gov search in October 2026 identified no trials specific to r(15) or to IGF1R haploinsufficiency; this result does not prove that no studies exist in other registries [107].

7.9. Developments in the last 12 months

In preclinical research, Kim and colleagues showed that reprogramming fibroblasts carrying ring chromosomes into induced pluripotent stem cells eliminates the ring and replaces it with a duplicated copy of the normal homologue (compensatory uniparental isodisomy), and proposed a future "chromosome therapy"; there is no human application [108]. For chromosome 15, a compensatory isodisomy would carry the additional risk of UPD in an imprinted region, a consideration that follows from the biology of 15q11-q13 [9].

7.10. Agents and situations to avoid

Mecasermin should not be used (see 7.5). GH is contraindicated in acute critical illness after open-heart or abdominal surgery, multiple trauma and acute respiratory failure, and should be suspended in these situations, and it should not be started in active neoplasia or with closed epiphyses [67]. The SGA guideline advises against GH in disorders with a high cancer predisposition, such as chromosomal instability syndromes and DNA repair defects, which makes it important to exclude Bloom syndrome in a picture of growth restriction with microcephaly and pigmentary changes [25, 74]. The sources consulted do not describe cancer predisposition in r(15), and the literature on the role of IGF1R in tumours refers to somatic overexpression, which does not apply to germline haploinsufficiency [7].

7.11. Pregnancy, lactation, perioperative care and transition

Women with r(15) are probably fertile, but pregnancy is high-risk because of short stature, a small uterus and the possibility of transmitting the ring; in the families described there were miscarriages and affected children [10, 28]. Paediatric GH is continued until final height and stopped according to the criteria in 7.2 [25, 92]. In the perioperative setting, the contraindication to GH in acute critical illness after major surgery means that it must be suspended [67]; the sources consulted do not describe specific anaesthetic recommendations for r(15), but the micrognathia, retrognathia and heart defects described should be taken into account in the pre-anaesthetic assessment [10, 24]. In the transition to adulthood, the patient of Guilherme and colleagues illustrates the problems that emerge: overweight with central obesity, acanthosis nigricans, subclinical hypothyroidism and eating behaviour disturbances [24]; the second SRS consensus emphasises the increased metabolic risk from adolescence to adulthood in disorders with prenatal growth restriction [72], and the SGA guideline includes, at the end of GH treatment, assessment of height, weight, blood pressure, thyroid function, lipids and bone age [25]. Adult autonomy is variable, from supported living to transition programmes [28].

7.12. Recommendations and divergences between sources

The sources diverge on four points. First, on the age at which GH is started: 2 years in the US labels, 4 years in the European and Portuguese SmPCs, and the age at which catch-up becomes unlikely (3–4 years in most) in the guideline [25, 67, 92]. Second, on the dose: the guideline starts at 0.033 mg/kg/day and allows increases up to 0.067 mg/kg/day, the European SmPC sets 0.035 mg/kg/day, and the IGF1R literature is divided between higher doses and absence of a dose–response relationship [25, 62, 69, 92]. Third, on the frequency of IGF-1 measurement: at 3–6 months and then at least annually in the guideline, and twice a year in the SmPC [25, 92]. Fourth, on eligibility: many regulatory criteria exclude dysmorphic syndromes, whereas the r(15) and 15q26 deletion literature recommends an individual therapeutic trial, with periodic reassessment [25, 62, 87]. In this article, the reference dose is that of the guideline and the labels serve for comparison.

8. Reproductive Options and Family Counselling

8.1. Origin of the ring and recurrence risk

r(15) usually arises de novo, through an error in gametogenesis or, more rarely, in the embryo [28]. For the class of rings, 99% of cases are sporadic, and in familial cases the mother is the transmitting parent in 90% [20]. When the parental karyotypes are normal (including a search for mosaicism in 30 cells), the recurrence risk is low, estimated at less than 1% for rings in general, with scarce data and a small possibility of germline mosaicism [20, 28]. When one parent is a carrier, the risk of transmission to each child is about 40% for rings in general [20].

Maternal transmission of r(15) is documented in several families: Fujimaki and colleagues described a mother and her two children with r(15) [109]; Horigome and colleagues, a mother and a 2-year-old son with r(15) and a normal son [19]; and Kalantari and colleagues, the first vertical transmission over three consecutive generations (a subfertile man, his mother and his newborn son) [18]. In the review by Chen and colleagues, six women with r(15) were fertile, with an increased risk of miscarriage and affected offspring, whereas four men were infertile and one had a child [10]. Unique emphasises that the ring affects the paternal or maternal chromosome 15 with equal probability [28].

In the offspring of parents with mosaicism for a ring, mosaicism with a normal cell line has been observed, a phenomenon that is difficult to explain and may correspond to opening of the ring (described by Speevak and colleagues in an inherited r(19); indirect attribution) [20]. Ring instability may also generate new rings in the next generation [21].

8.2. Male fertility

Rings in general are associated with male subfertility [20]. In the men with r(15) described, cryptorchidism, genital hypoplasia, oligozoospermia, asthenozoospermia and azoospermia predominate, and some were diagnosed because of infertility [10, 28, 110]. Nishikawa and colleagues injected motile spermatozoa from a man with severe oligozoospermia and r(15) into enucleated mouse oocytes: the pronuclei analysed had a normal karyotype and none contained the ring, and fertilising capacity decreased with the aspect ratio of the sperm head (85.2%, 76.2% and 64.3%); the authors interpret the result as selection against ring-bearing spermatozoa, with the limitation that it concerns a single patient [65]. Kalantari and colleagues documented paternity in an infertile man with r(15), whose son inherited the ring [18].

8.3. Prenatal diagnosis and preimplantation genetic testing

After a child with de novo r(15), chorionic villus sampling or amniocentesis may be offered for reassurance [20]; Unique recommends discussing amniocentesis in the next pregnancy, because the ring is visible in amniocytes [28]. With a finding of mosaicism for a ring or marker in chorionic villi, interpretation follows the rules of prenatal mosaicism, and the recurrence risk is negligible when the mosaicism results from mitotic non-disjunction [71]. When one parent is a carrier, prenatal diagnosis should include karyotyping (for the ring and mosaicism) and microarray (for the deletion) [20, 23]. Ultrasound has limitations: the fetal findings described (FGR, CDH, nuchal fold, heart disease) are concentrated in severe cases, and a normal scan does not exclude r(15) [44].

The 2020 ESHRE (European Society of Human Reproduction and Embryology) good practice recommendations for preimplantation genetic testing for structural rearrangements (PGT-SR) describe the available techniques (FISH, aCGH, SNP microarray, next-generation sequencing) and their limitations: FISH does not distinguish a balanced from a normal embryo and does not detect UPD, and segments below the resolution or with breakpoints near the telomere may escape aCGH [111]. The document does not deal specifically with ring chromosomes; its application to a woman or a man with r(15) is an extrapolation, in which a 15q26 deletion of several megabases is within reach of genomic techniques, but ring mosaicism and UPD 15 require specific test design [111].

8.4. Counselling

Counselling should address the variability of the phenotype (determined by the extent of the deletion, mosaicism and ring instability), the absence of causal treatment, the modest and variable results of GH and the reproductive risk of the patients themselves [10, 20]. The annotated photograph of the ring and a three-generation pedigree, with questions about the health, development and schooling of the parents, are useful tools [20]. In adolescents and adults with learning difficulties, reproductive counselling requires adequate time and appropriate consent; the decision about prenatal diagnosis for a familial ring should take these circumstances into account [20]. When one parent carries the ring, study of siblings and other relatives follows the parental karyotype [20]. In IGF1R defects with dominant transmission, parental height and HC guide the segregation analysis, and carrier parents may have only short stature [5, 7].

As for supernumerary chromosome 15 markers, de novo cases have a very low recurrence risk, and familial ones have a high transmission risk, rarely with an abnormal phenotype [9].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

There is no population estimate of the prevalence or incidence of r(15). The available figures measure different things. Orphanet classifies point prevalence as below 1/1,000,000 and cites about 50 described cases, from Glass and colleagues (2006) [1, 41]. The reviews of published cases count 97 cases up to 2018, 89 up to 2022 (Alhashem, according to their search) and 116 up to March 2021 (Chen), figures that reflect the literature and not the frequency in the population [10, 21, 22]. For the class of rings, Orphanet gives a birth prevalence of 1–9/100,000 (mean 2.0/100,000), attributed to Jacobs and colleagues (1975) [2]; the abstract of that study, which analysed reproductive fitness in families with structural aberrations, does not present the estimate, and the full text was not consulted [81]. For distal 15q deletion, Orphanet cites about 30 cases (Rudaks 2011) [4, 80]. For IGF1R defects, the SGA guideline estimates a frequency of 1–2% among SGA children with short stature, a proportion in a selected population and not a prevalence [25]; GeneGuidance does not identify a substantiated population prevalence [7].

Some people with r(15) may never have been diagnosed, especially adults with a mild phenotype [28]; the diagnosis of a 30-year-old woman because of infertility illustrates this possibility [42]. In the reviews, females predominate (40 to 24 in the Chen series), with no known explanation [10, 18].

9.2. Geographical distribution of published cases

Published cases come from all continents, with no founder effect described. In Europe, there are cases and series from Finland, Denmark, Sweden and Germany, Hungary, Poland, Italy, the Netherlands and the United Kingdom [13, 40, 50, 60, 61, 87, 88]; in the USA, the first clinical and molecular series [36, 38, 41] and the case of sSMC r(15) with UPD [8]. Outside these regions there are cases from China, Japan, Taiwan, Thailand, Iran, Saudi Arabia, Tunisia, Turkey, Ecuador and Argentina [10, 18, 19, 21, 22, 43, 44, 58, 63, 69, 86]. The Ecuadorian case is that of a mixed-ancestry infant from the Amazon region, in a population with an estimated ancestry of 63.1% Native American, 30.3% European and 6.6% African [21].

Brazil has contributed several studies: the molecular study of distal 15q with participation from Curitiba (Rogan 1996) [39], the study of in vivo resistance to IGF-1 in Curitiba (De Lacerda 1999) [47], the 20-year cytogenetic and molecular follow-up in São Paulo (Guilherme 2012) [24], prenatal diagnosis by three-dimensional ultrasound in São Paulo (Britto 2014) [64] and the scientific review of the Unique guide by a researcher from the Federal University of São Paulo [28]. From Portugal, the sources consulted include a case of biallelic IGF1R defect with prenatal diagnosis (Sá Pinto 2026) [51]; no Portuguese cases of r(15) were found in the sources consulted, which does not demonstrate that none exist.

9.3. Special populations

In women with r(15), pregnancy requires obstetric surveillance because of short stature, the uterine hypoplasia described and the risk of transmission and miscarriage [24, 28]. Adults with intellectual disability require adaptations in communication and consent [20]. Patients with a mild phenotype and mosaicism may come to medical attention only because of infertility [42].

9.4. Reference networks and patient associations

In the European Union, patients can be referred to ERN ITHACA (European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders), which has working groups on neurodevelopmental disorders and fetal medicine and its own registry [26], and to Endo-ERN (European Reference Network on Rare Endocrine Conditions), through the main thematic groups on growth and genetic obesity syndromes (MTG5) and on sex development and maturation (MTG7) [27]. The British association Unique (Rare Chromosome Disorder Support Group) publishes a guide for families on r(15), compiled in 2004 and revised in 2018 [20, 28]. Chromosome Disorder Outreach, in the USA, supports families with chromosomal disorders, with materials in English, Spanish and Arabic; in Brazil, Instituto Vidas Raras supports people with rare diseases, with no content specific to r(15) identified [29]. The Orphanet page for r(15) is ORPHA:96177 [1].

10. Illustrative Clinical Case

Guilherme and colleagues, from the Federal University of São Paulo, published in 2012 the 20-year cytogenetic and molecular follow-up of a woman with r(15) [24]. She was the third child of healthy, non-consanguineous parents (Caucasian mother, father of Asian origin), with four siblings. At birth she weighed 2050 g (below the 5th centile), measured 48 cm (5th centile) and had an HC of 30 cm (below −2 SD).

At the first genetic assessment, at 8 years and 10 months, she measured 106 cm and weighed 17 kg (both below the 5th centile), with an HC of 48 cm (below −2 SD). She had microcephaly, brachycephaly, high forehead, exotropia, hypoplastic alae nasi, high palate, retrognathia, hyperextensible knees, dry and rough skin on the lower limbs, generalised hirsutism, four café-au-lait macules, small disseminated hypopigmented macules and dorsolumbar scoliosis; intellectual disability was mild, with a reduced verbal repertoire and a docile and cooperative personality. The G-banded lymphocyte karyotype (1989) showed a ring chromosome 15 in place of a normal chromosome 15; silver staining identified the nucleolar organiser region on the ring, and the parental karyotypes were normal [24].

At 27 years and 3 months, the patient measured 146.5 cm (below the 3rd centile; −2.6 SD according to the review by Chen and colleagues), weighed 58 kg (body mass index 27.23 kg/m²) and still had an HC of 51.5 cm (below −2 SD). She had central obesity, sparse and fine hair, left exotropia, thin upper lip, hypoplastic proximally placed thumbs, disseminated leaf-shaped hypopigmented macules, acanthosis nigricans, dry skin and subclinical hypothyroidism; she had had regular menstruation since 14 years. Behaviourally, she showed compulsive eating and aggression when thwarted, and could not read or write [10, 24]. She never received GH.

Repeated cytogenetic study of 300 metaphases showed cells with loss of the ring or with secondary aberrations (two monocentric rings, interlocked rings, dicentric ring, broken or open ring) in 4.7% at 8 years and in 7.7% at 28 years, that is, dynamic mosaicism with a slight increase over 20 years. The SNP microarray (Affymetrix 6.0, hg18) defined the karyotype as 46,XX,r(15)(p13q26.2)dn.arr 15q26.2q26.3(94,810,000-100,338,900)×1: a 5.5 Mb terminal deletion with 25 genes, including IGF1R. The microarray did not detect the dynamic mosaicism visible on the karyotype [24]. Figure 1 of the article (partial karyotype with the ring, two monocentric rings, open ring, centromeric FISH with a dicentric ring and microarray plot with the terminal deletion) is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC3459701/figure/F1/ [24].

The case brings together the central elements of this article: growth restriction of prenatal onset without catch-up, persistent microcephaly, mild intellectual disability, mosaic pigmentary changes, adult height close to −2.6 SD without treatment, preserved female gonadal function, metabolic and behavioural problems in adulthood and the demonstration that only karyotyping reveals ring instability. The absence of GH reflects the date of diagnosis and not a recommendation; current management would follow the SGA guideline (section 7.2).

A second case, from Chen and colleagues, illustrates treatment: a Chinese girl with a birth weight of 2000 g and length of 42 cm, VSD operated on at 6 years, height of 126.9 cm (−3.45 SD) at 11.5 years, IGF-1 of 448 ng/mL, central puberty under way and karyotype 46,XX,r(15)[20] with a 4.5 Mb deletion in 15q26.2-q26.3 (including IGF1R and MEF2A, with NR2F2 intact). She received GH 1.33 mg/day (about 0.033 mg/kg/day for a weight of 40 kg) with triptorelin 3.75 mg monthly; in six months she grew 3.8 cm (velocity 7.6 cm/year) and IGF-1 rose to 1077 ng/mL at 3 months, with no adverse effects reported, with follow-up of less than one year [10]. The figures in the article show the short fifth metacarpal and the café-au-lait macules (https://pmc.ncbi.nlm.nih.gov/articles/PMC8683626/figure/mgg31842-fig-0001/) and the microarray results of patients with 15q26 deletion and r(15) (https://pmc.ncbi.nlm.nih.gov/articles/PMC8683626/figure/mgg31842-fig-0003/) [10]. The IGF-1 of 1077 ng/mL exceeds the upper reference limit given by the authors (693 ng/mL), which diverges from the SGA guideline recommendation to keep IGF-1 up to +2 SD [10, 25].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

There are no data on survival or life expectancy in r(15). Vital prognosis is determined mainly by the malformations: in fetuses with CDH and FGR diagnosed prenatally, the published outcomes were termination of pregnancy, intrapartum fetal death or neonatal death in the first hours [44, 64]. Outside these forms, adults with r(15) have been described at various ages, including a 31-year-old woman living independently [41], a 45-year-old adult in supported living after supervised work [28] and the patient of Guilherme and colleagues followed up to 28 years [24].

Adult height without GH lies between −6.8 and −2.5 SD in published cases [10], and Unique expects about 152 cm in most [28]. With GH, the mean gain in the series is about +1 SD, without complete catch-up in most; the best individual results published are 164 cm (−1.4 SD) in a boy and −2.1 SD in a girl treated from 1.8 years for 12.4 years [10, 69, 87]. Cognitive development is stable over time: in the Fryns follow-up, IQ remained stable, the marked verbal difficulties between 4 and 6 years disappeared and social adaptation was normal; in a mosaic patient followed for 29 years, the clinical course and ring stability in several tissues were maintained (indirect attributions, according to Guilherme and colleagues) [24]. Dynamic mosaicism may increase slightly with age (from 4.7% to 7.7% over 20 years) [24]. In adulthood, overweight, metabolic changes and eating behaviour disturbances appear [21, 24]. In adult carriers of IGF1R variants, a survey showed no excess comorbidity compared with adults born SGA, with a small sample [62].

11.2. Surveillance

There is no specific surveillance guideline for r(15). The following table combines surveillance from the SGA guideline and the SmPCs during GH, which has published intervals, with assessment targeted at the frequent manifestations of r(15), for which there are no published intervals and which follows general paediatric practice.

12. Summary and Final Considerations

Ring chromosome 15 syndrome is a rare chromosomal anomaly, with about a hundred published cases, in which a circular chromosome 15 replaces one of the homologues. The phenotype results from the sum of two components: monosomy of terminal 15q, which in most patients includes IGF1R, a gene with demonstrated haploinsufficiency, and the mitotic instability common to all rings, which generates dynamic mosaicism and contributes to growth restriction even when IGF1R is retained. Growth restriction of prenatal onset, microcephaly, mild to moderate intellectual disability with speech delay and café-au-lait macules associated with hypopigmented macules form the clinical core; heart disease, urogenital malformations and CDH occur in a minority and concentrate the risk to life.

Diagnosis requires two techniques: microarray, which defines the deletion and the genes lost, and karyotyping, which demonstrates the ring, mosaicism and instability and distinguishes the ring from a simple terminal deletion or an unbalanced translocation. Microcephaly separates r(15) from Silver-Russell syndrome, which the second international consensus now defines by molecular criteria; a normal or high IGF-1 points to IGF-1 resistance and argues against IGF-1 deficiency.

There is no causal treatment. Growth hormone, used by extrapolation from the SGA indication at the dose of the 2023 guideline (start at 0.033 mg/kg/day, up to 0.067 mg/kg/day, with IGF-1 up to +2 SD), produces mean gains of about +1 SD, which are variable and smaller than those of SGA children without an IGF1R defect, with monitoring of glucose and insulin. Mecasermin is not indicated. Weekly somapacitan was approved in the USA for SGA children in February 2026 and received a positive CHMP opinion in September 2026, with no data in r(15). Follow-up is multidisciplinary, with cardiac, renal, auditory, visual, orthopaedic and developmental assessment.

Most cases are de novo, with a low recurrence risk after parental mosaicism has been excluded. Women with r(15) are generally fertile and may transmit the ring; men are generally infertile, although paternal transmission has been documented. The absence of a population prevalence, of specific trials and of a dedicated guideline are the main gaps in current knowledge.

13. References

1. Orphanet. Ring chromosome 15 syndrome (ORPHA:96177). Available from: https://www.orpha.net/en/disease/detail/96177
2. Orphanet. Ring chromosome syndrome (ORPHA:363203). Available from: https://www.orpha.net/en/disease/detail/363203
3. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 612626: Chromosome 15q26-qter deletion syndrome (Drayer syndrome). Available from: https://omim.org/entry/612626 (accessed Oct 2026)
4. Orphanet. Distal deletion 15q syndrome (ORPHA:1596). Available from: https://www.orpha.net/en/disease/detail/1596
5. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 270450: Insulin-like growth factor I, resistance to; IGF1RES. Available from: https://omim.org/entry/270450 (accessed Oct 2026)
6. Orphanet. Growth delay due to insulin-like growth factor I resistance (ORPHA:73273). Available from: https://www.orpha.net/en/disease/detail/73273
7. GeneGuidance. IGF1R — Insulin-like growth factor-1 receptor. Accessed 2026-09-26.
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