3M Syndrome (3M Syndromes Types 1, 2 and 3)

Literature and regulatory information updated: 29 October 2026.

3M syndrome (Miller-McKusick-Malvaux syndrome; Le Merrer syndrome; Yakut short stature syndrome), an autosomal recessive primordial growth disorder caused by biallelic variants in CUL7, OBSL1 or CCDC8, the three components of the 3M ubiquitin ligase complex. It includes the historical entities "dolichospondylic dysplasia" and "gloomy face syndrome". The differential diagnosis with Silver-Russell syndrome, Mulibrey nanism and the other forms of prenatal-onset dwarfism is covered in section 6.

0. Initial Reference Table

1. Introduction

1.1 Original description and origin of the name

3M syndrome is a primordial growth disorder, that is, a condition in which the reduction in body size begins in utero and persists throughout life, without any maternal, placental or endocrine disease to explain it [3, 15]. The first description is attributed to Fuhrmann and colleagues, who in 1972 reported a family with short stature and disproportionately tall vertebrae [15]. The delineation that gave the entity its name was published in 1975 by Miller, McKusick, Malvaux, Temtamy and Salinas, under the title "The 3-M syndrome: a heritable low birthweight dwarfism", and the designation "3-M" derives from the initials of the surnames of the first three authors [4, 15, 20]. The first patients in that article were a brother and sister, the children of first cousins, with low birthweight dwarfism, a narrow face, a groove in the lower part of the anterior chest wall, clinodactyly and normal intelligence [8]. Spranger, Opitz and Nourmand described in 1976 a family with intrauterine growth restriction that they recognised as the same condition, and Hennekam, Bijlsma and Spranger published a review in 1987 that consolidated the phenotype [4]. In 1991, Le Merrer, Brauner and Maroteaux described "dwarfism with gloomy face", which turned out to be the same disease, which is why 3M syndrome is also called Le Merrer syndrome [2, 4].

1.2 Milestones of the molecular discovery

In 2005, Huber and colleagues studied 29 families, mapped the responsible gene to 6p21.1 and identified 25 distinct variants in CUL7, which encodes cullin 7, a scaffold protein of an E3 ubiquitin ligase complex [21]. The functional assays in that work showed that a disease-associated nonsense variant and a missense variant prevented cullin 7 from recruiting the ROC1 protein, impairing ubiquitination, and the authors proposed that defective ubiquitination may contribute to human intrauterine growth restriction [21]. In 2009, the same French team studied 33 new patients and found CUL7 variants in 23; in the remaining 10 there was no variant, and in six consanguineous families the 6p21.1 locus was excluded, demonstrating genetic heterogeneity [22]. In the same year, Hanson and colleagues, by single nucleotide polymorphism mapping in patients without CUL7 variants, identified a second locus at 2q35–q36.1 and seven null variants in OBSL1 in ten families, and showed that loss of OBSL1 reduces cullin 7 levels [23]. Huber and colleagues independently reached the same gene and described nine OBSL1 variants in 13 families, with altered expression of the insulin-like growth factor binding proteins IGFBP2 and IGFBP5 in fibroblasts [24]. In 2011, exome sequencing identified CCDC8 as the third gene, with a physical interaction between CCDC8 and OBSL1 demonstrated by co-immunoprecipitation, and the authors proposed that CUL7, OBSL1 and CCDC8 belong to a single growth control pathway [25]. In 2014, Yan and colleagues showed that the three proteins form a complex, called the 3M complex, which maintains microtubule and genome integrity [26], and in 2019 Wang and colleagues showed that this complex assembles at the plasma membrane starting from CCDC8 and identified its first physiological substrate, the protein LL5β [27].

1.3 Nomenclature and classification

OMIM divides the disease into three entries according to the affected gene: 3M syndrome type 1 (3M1, CUL7, #273750), type 2 (3M2, OBSL1, #612921) and type 3 (3M3, CCDC8, #614205) [2, 8]. This division does not correspond to reliable clinical or radiological differences between the forms, as the skeletal dysplasia atlas of Spranger and colleagues emphasises [4]. The 2023 revision of the Nosology of genetic skeletal disorders, from the International Skeletal Dysplasia Society, adopted the dyadic nomenclature, which links the phenotype to the gene of origin ("3-M syndrome, CUL7-related", "OBSL1-related" and "CCDC8-related"), and placed 3M syndrome in group 21, the group of primordial dwarfism and slender bones, alongside Sanjad-Sakati syndrome, Kenny-Caffey syndrome, osteocraniostenosis, microcephalic osteodysplastic primordial dwarfism, IMAGe syndrome and Saul-Wilson syndrome [1]. In 1989, Flannery proposed calling the disease "dolichospondylic dysplasia" because of the tall vertebrae, and Spranger objected that tall vertebrae are a non-specific manifestation of hypotonia and that the skeletal changes of primordial dwarfism reflect hypoplasia rather than dysplasia [8]. The same 2023 revision incorporates into the CUL7-related form the entities formerly called dolichospondylic dysplasia and Yakut short stature syndrome [1, 2]. Orphanet maintains a single entity, ORPHA:2616, for the three genes, and defines it as a rare primordial growth disorder with low birth weight and length, severe postnatal growth restriction, a head that is large relative to the body, a spectrum of minor anomalies including facial dysmorphism, and normal intelligence [3].

1.4 Operational definition and scope

Throughout this article, 3M syndrome refers to the disease caused by biallelic pathogenic or likely pathogenic variants in CUL7, OBSL1 or CCDC8, or to the characteristic clinical and radiological picture in patients without a molecular diagnosis [2]. The three forms are covered together, because they share the mechanism and the phenotype, and differences between genes are indicated where data exist (stature, frequency of some signs, response to growth hormone) [2, 14]. Silver-Russell syndrome, the main differential diagnosis, Floating-Harbor syndrome, Temple and Kagami-Ogata syndromes, Seckel syndrome, microcephalic osteodysplastic primordial dwarfism and the general approach to short stature are included in the differential. Mulibrey nanism, caused by variants in TRIM37, is described in detail in section 6 because it is the differential with the greatest clinical impact.

2. Molecular Genetics and Pathophysiology

2.1 The three genes and their proteins

CUL7, at 6p21.1, encodes cullin 7, a large protein that acts as a scaffold for the assembly of an E3 ubiquitin ligase: it binds the small RING domain protein ROC1 and, through its central region, the Skp1-Fbx29 heterodimer (also called FBXW8), forming the CUL7-RING(FBXW8) complex [2, 21]. Cullin 7 is cytoplasmic, localises to the centrosome and is required for anaphase and telophase, because it regulates microtubule dynamics [2]. It also interacts with p53, cyclin D1 and insulin receptor substrate 1 (IRS-1), a downstream effector of the growth hormone and IGF-1 receptors; this last interaction has been proposed as the basis of part of the resistance in the growth hormone axis observed in patients [28, 29]. OBSL1, at 2q35, encodes obscurin-like protein 1, a cytoskeletal adaptor of the Unc-89/obscurin family, made up of immunoglobulin-like domains at the N- and C-terminal ends and a central fibronectin type 3 domain [30]; it localises to the nuclear envelope and maintains cullin 7 levels [23, 26]. CCDC8, at 19q13.32, encodes a ubiquitously expressed coiled-coil domain protein that interacts physically with OBSL1 but not directly with cullin 7, and that has also been described as a cofactor of p53-mediated apoptosis after DNA damage [25, 28]. CCDC8 consists of a single exon [2].

2.2 The 3M complex and the cellular mechanism

Yan and colleagues showed in 2014 that OBSL1 and CCDC8 form a complex with cullin 7: OBSL1 regulates the level of cullin 7 and CCDC8 is required for its localisation to the centrosome [26]. Depletion of cullin 7 in cells alters microtubule dynamics and causes prometaphase arrest, tetraploidy and mitotic death; these defects are reproduced in cells from patients with CUL7 variants and are corrected by normal cullin 7 but not by the patients' mutant forms, and depletion of OBSL1 or CCDC8 produces similar defects and makes cells sensitive to microtubule damage [26]. In 2019, Wang and colleagues showed that CCDC8, a protein derived from a retrotransposon Gag protein exclusive to placental mammals, localises to the plasma membrane; after phosphorylation by the kinases CK2 and GSK3, it binds first to OBSL1 and then to cullin 7, assembling the 3M E3 complex at the membrane [27]. The substrate identified was LL5β, a membrane protein that regulates cell migration. Inhibition of CCDC8 phosphorylation by the Wnt pathway, or the patients' variants in the three genes, disrupt the membrane localisation of the complex and lead to accumulation of LL5β, and Ccdc8-null mice have impaired trophoblast migration and placental development, with intrauterine growth restriction and perinatal lethality [27]. These data link the molecular defect to growth restriction of placental and fetal origin. Maksimova and colleagues had described, in the Yakut population, abnormal vascularisation of the fetal placenta and abnormal development of bronchial cartilage in a fetus with a CUL7 variant [31]. GeneReviews summarises the disease mechanism as loss of function [2].

2.3 The growth hormone and insulin-like growth factor axis

Children with 3M syndrome usually have normal serum growth hormone (GH) and normal or low IGF-1, and the response to recombinant GH is variable; taken together, this suggests a degree of resistance in the GH-IGF axis [15, 28]. Hanson and colleagues studied patient fibroblasts in 2012: in cells lacking cullin 7, activation of STAT5b and MAPK kinase in response to GH was normal, but activation of AKT in response to IGF-1 was reduced; in cells lacking OBSL1, both pathways were reduced; in cells lacking CCDC8, the response to GH was reduced and the response to IGF-1 was normal [32]. The authors interpreted these results as IGF-1 resistance in the CUL7 forms, combined resistance in the OBSL1 forms and GH resistance in the CCDC8 forms, and described dysregulated production of IGF binding proteins by 3M cells [32]. OBSL1 variants modulate the expression of IGFBP2 (decreased) and IGFBP5 (increased) [24]. 3M syndrome is also associated with reduced expression of IGF2 and increased expression of H19, a pattern also described in Silver-Russell syndrome [17]. An interaction network study identified 131 proteins associated with the complex, with messenger RNA processing as the most represented pathway, and showed altered alternative splicing of exon 11 of the insulin receptor, with a reduction in the mitogenic isoform; the authors presented these data as preliminary [33]. Clayton and colleagues also reported that potentially deleterious CUL7 and OBSL1 variants have been found in children with idiopathic short stature, including children born small for gestational age without catch-up growth, suggesting a broader role of the pathway in growth disorders [28]. Some authors have proposed that 3M syndrome is a ciliopathy, because the genes participate in ciliogenesis and patient fibroblasts have fewer cilia; this hypothesis is cited by Ozturk and colleagues as a possible explanation for male hypogonadism, without confirmation [29].

2.4 Variant spectrum

According to GeneReviews, sequencing detects all the variants described in the three genes and no intragenic deletions or duplications have been reported [2]. In CUL7, null variants (nonsense and splicing) predominate, but missense variants are also frequent; half are located in the cullin domain, required to anchor ROC1, and the rest are distributed along the gene [2, 34]. In OBSL1, most variants lie in the first eight exons, affecting all known isoforms, with a predominance of loss of function [2]. In CCDC8, the variants described in GeneReviews lead to protein truncation [2]; the review by Bacchi and colleagues, which compiled the cases published up to March 2025, classified CCDC8 variants as usually missense, and this discrepancy reflects the small number of cases (12 patients) [14]. In the same review, CUL7 variants were mainly frameshift and nonsense, followed by splicing and missense, with more small deletions than duplications; in OBSL1, frameshift and nonsense variants also predominated, with a slight excess of duplications [14]. Huber and colleagues found a patient with paternal uniparental isodisomy of chromosome 6 that made homozygous a CUL7 variant inherited from a single parent [22]. Cases without a variant in the three genes suggest other genes yet to be identified [2, 22], and two children with a similar phenotype had a de novo deletion at 20p13p including BMP2, a phenocopy with features of its own [35].

2.5 Founder variants and nomenclature

The variants below were normalised in VariantValidator on the GRCh38 assembly and the MANE Select transcripts (CUL7 NM_014780.5; OBSL1 NM_015311.3) [6]. The historical nomenclature is kept in parentheses because the literature of each population uses it.

The example of Deeb and colleagues illustrates the errors of historical notation: the variant was published as "c.263delT" with the protein consequence "p.val88Ala" on version NM_014780.4, but the single-nucleotide deletion corresponds, on the MANE transcript, to NM_014780.5:c.263del, p.(Val88AlafsTer27), a frameshift variant and not a missense variant [6, 37]. In Turkey, in addition to OBSL1 c.1273dup, OBSL1 c.1277_1282+5del (three families) and CUL7 c.1938dupG (three families) recur in the Istanbul series [29]. Gene frequency differs between populations: OBSL1 accounts for 44% to 75% of families in the Turkish series, far above the early European series, which has been attributed to the founder effect of c.1273dup [29, 35].

2.6 Genotype-phenotype correlations

GeneReviews and the skeletal dysplasia atlas conclude that the CUL7 and OBSL1 forms are clinically and radiologically indistinguishable, with one quantitative exception: patients with CUL7 variants are shorter [2, 4]. In the Turkish series of Akalın and colleagues (25 patients, 19 families), patients with CUL7 had a significantly lower height standard deviation (SD) score at admission and at the last assessment and a lower weight SD score at the last assessment, with no difference in birth weight or length [16]; Simsek-Kiper and colleagues found significantly lower birth weight and height at admission with CUL7 [35]; Hanson and colleagues observed the same in a series of 13 families [32]. The series of Ozturk and colleagues (24 patients) found no significant height differences between genes (median −5 SD with CUL7 and −4.1 SD with OBSL1; p=0.1) [29]. The review of 217 cases by Bacchi and colleagues, excluding Yakut patients, showed a mean height at first description of −5.32 SD with CUL7, −4.49 SD with OBSL1 and −4.34 SD with CCDC8, and recorded intellectual disability only in patients with OBSL1 variants, a finding the authors relate to the role of OBSL1 in Golgi morphogenesis and dendritic arborisation [14]. Yakut patients homozygous for CUL7 c.4581dup differ from other patients with CUL7: they have more neonatal respiratory distress (41.9% with asphyxia and respiratory distress at birth, of whom 25.6% were ventilated) and far fewer radiological findings (slender long bones in 2% versus 79%; tall vertebral bodies in 9% versus 63%; widened metaphyses in 26% versus 91%), as well as less clinodactyly (9% versus 62%) [2, 14, 31]. In the five probands with CCDC8 variants described by Hanson and colleagues, all born to consanguineous parents of Asian origin, the fleshy nasal tip, short thorax and prominent heels were always present, whereas tall vertebrae and slender long bones were less frequent [12]. One study suggested a better response to GH in the CCDC8 forms, without sufficient data to confirm it [2]. Within the same family and with the same variant, birth weight, dysmorphic features and GH-IGF axis parameters may differ [29, 37].

2.7 Penetrance, carriers and allelic disorders

Heterozygotes are usually asymptomatic [2]; García-Cruz and Cantú described in 1979 mild features in presumed heterozygotes, an observation not confirmed in the molecular series consulted [8]. No other phenotypes associated with germline variants in CCDC8, CUL7 or OBSL1 are known [2].

3. Clinical Spectrum and Manifestations by System

3.1 Prenatal and postnatal growth

Severe intrauterine growth restriction is the most constant feature of 3M syndrome [2]. Birth length at term lies between 40 and 42 cm according to GeneReviews and between 35 and 42 cm according to the skeletal dysplasia atlas, with normal head circumference for gestational age [2, 4]. Smith's Recognizable Patterns of Human Malformation gives a mean length of 40.5 cm and a mean weight of 2120 g at term, in the absence of maternal or placental disease [15]. In the series with quantitative data, the mean birth length SD score was −4.3 in 19 Turkish patients followed from early childhood [38], the median birth weight SD score was −3.8 (−6.3 to −1.4) in 24 patients from Istanbul, all but one small for gestational age [29], and the mean birth weight SD score was −3.02 with CUL7, −2.69 with OBSL1 and −3.43 with CCDC8 in the review of 217 cases [14]. The international consensus on children born small for gestational age (SGA) attributes to 3M syndrome a mean birth weight and length SD score of −3.1 [17]. There is no catch-up growth after birth: height remains several standard deviations below the mean, weight is below the 3rd centile for age but relatively high for height, the upper-to-lower segment ratio is slightly increased, bone age is delayed or normal and the head appears large relative to the body [2, 15]. The short stature is proportionate [2, 4]. In the Istanbul series, the median height SD score at admission was −4.1 (−7.9 to −2.7), that of head circumference −0.2 and that of body mass index −0.5, and bone age was delayed in 21 of the 24 patients [29]; in the review of 217 cases, the mean height SD score at first description was −5.32 (CUL7), −4.49 (OBSL1) and −4.34 (CCDC8), and two patients with OBSL1 had normal height [14]. Feeding difficulties are frequent in the first year, and some children need early nutritional support [2, 15].

3.2 Adult height

Final height ranges from 115 to 150 cm, that is, between −8 and −4 SD, according to Smith [15], and lies 5 to 6 SD below the mean for age and sex according to GeneReviews and the Oxford Desk Reference [2, 39]. In eight Turkish patients who reached final height, the mean was −4.9 SD [38]. In individual patients, adult heights of 117 cm (−6.71 SD in the abstract and −7.04 SD in the text of the same article) in an Emirati woman who was never treated [37] and of 105 cm (−8.4 SD) in an untreated Saudi woman diagnosed at the age of 20 years [7] have been described. A comparison of six Dutch patients with 28 from the literature showed a growth pattern parallel to that of Silver-Russell syndrome, but with final height about 1 SD lower [40]. The SGA consensus stresses that not all patients have such severe restriction and that there are cases with milder intrauterine restriction [17, 34].

3.3 Face and skull

In infancy, the head is relatively large, with dolichocephaly, prominent forehead, triangular face, midface retrusion, thick eyebrows, fleshy or bulbous nasal tip, anteverted nares, long philtrum, thick vermilion of both lips and pointed chin; facial naevus simplex and infraorbital fullness may be present [2, 15]. The skeletal dysplasia atlas also describes mild hypertelorism, prominent, wide-open eyes with periocular fullness (the "gloomy" appearance that gave gloomy face syndrome its name), full lips and prominent ears [4]. Tüysüz and colleagues, who followed 19 patients for 2 to 20 years, described three early signs: infraorbital swelling of the lower eyelid and facial infantile haemangioma, which fade with age, and a central tubercle of the upper lip, which becomes more pronounced [38]. With growth, the triangular face, long philtrum and pointed chin become more marked and the naevus simplex and infraorbital fullness disappear [2]; the atlas describes normalisation of the face in late childhood and adulthood [4]. Bacchi and colleagues, after reviewing published photographs, considered the morphology of the nose, with a bulbous tip, anteverted nares and a frequently concave root, to be the most persistent facial sign [14]. Tooth eruption may be delayed, and a V-shaped dental arch with anterior crowding and malocclusion and caries have been described [15]; dental changes and crowding were frequent in the Saudi series [7].

3.4 Thorax, spine and limbs

The neck is short and broad, with prominent trapezius muscles and horizontal clavicles that give a square-shouldered appearance; the thorax is short, with pectus carinatum or excavatum, and the scapulae may be winged [2, 15]. Transverse grooves in the lower part of the rib cage are described in several series [2, 38]. The spine shows lumbar hyperlordosis, thoracic kyphoscoliosis and, sometimes, spina bifida occulta [2]. In the limbs, there is fifth-finger clinodactyly, a single transverse palmar crease, generalised or distal joint hypermobility, flat feet and prominent heels with a fleshy posterior protrusion [2, 15]. A prominent abdomen, with diastasis recti, is frequent and persists discreetly in the older child [14, 15].

Developmental dysplasia of the hip and congenital dislocation of the hip are the orthopaedic complications with the greatest consequences. Badina and colleagues described two patients diagnosed with 3M syndrome at birth who presented at 10 and 20 months with bilateral hip dislocation, noted that small size makes hip examination difficult and that ligamentous laxity may predispose to dislocation and complicate treatment, and recommended referring these patients to paediatric orthopaedics soon after birth [2, 8, 41]; bilateral congenital dislocation has been described in Tunisian patients [36], and in the Istanbul series 25% of patients had joint disease (hip dysplasia in 16%, Perthes disease or juvenile idiopathic arthritis in the rest) [29]. An untreated adult Saudi woman had severe hip dysplasia with pseudoacetabulum formation [7]. In the review of 217 cases, hip dislocation was recorded in 19% of patients with CUL7, 3% with OBSL1 and 20% with CCDC8, and scoliosis in 18%, 27% and 17% [14]. Elbow dysplasia with reduced extension, short ulna, recurrent knee dislocations and genu valgum have also been described [2, 5, 15].

3.5 Frequency of signs by gene

The review by Bacchi and colleagues brought together the patients with molecular confirmation published up to March 2025 and excluded Yakut patients from the frequency calculations, because they form an isolate with a single variant and fewer radiological findings [14]. Denominators vary because not all signs were assessed in all patients, and some were inferred from published photographs.

Source: table 1 of Bacchi and colleagues, excluding Yakut patients [14].

3.6 Neonatal period and respiratory system

A small proportion of infants have significant respiratory distress and/or recurrent respiratory infections that may be life-threatening [2]. In the Yakut population, 41.9% of patients homozygous for CUL7 c.4581dup had asphyxia and respiratory distress at birth, and 25.6% of these required mechanical ventilation [2, 31]. In an Emirati family with homozygous CUL7 variants, two sisters died at 9 and 12 months after recurrent respiratory infections, with a narrow thorax on radiography, and a maternal branch of the family had two further deaths in infancy from respiratory failure; the authors present early death from respiratory failure in a sibship as a diagnostic clue [37]. An Italian newborn required high-flow oxygen for two days [14]. In the same population, in 5 families (11.6%) there were affected newborns who died shortly after birth from an unknown cause [8]. The skeletal dysplasia atlas records significant neonatal constipation as an under-recognised recurrent feature [4].

3.7 Endocrinology, puberty and reproduction

Most children are assessed for GH deficiency. Only a small proportion have partial or significant deficiency, and a growing number have GH insensitivity, demonstrated by the absence of an IGF-1 rise in the generation test [2]. In the Istanbul series, the stimulation test was performed in 20 of the 24 patients: 9 had a GH peak above 10 ng/ml (exaggerated response in 5) and 8 had a low response, IGF-1 was low, normal or high, and IGFBP-3 was below −2 SD in 2 of 22 patients; thyroid and adrenal function were normal and coeliac disease serology was negative [29]. In a Turkish series of eight patients with OBSL1 variants, the response to the stimulation test was sufficient in five [42]. In the Saudi series, IGF-1 was normal or at the lower limit in most and raised in two [7].

In boys, gonadal dysfunction with subfertility or infertility is documented by raised FSH, low testicular volume and abnormal semen analysis, and some have hypospadias; female gonadal function is normal [2, 15, 40]. Ozturk and colleagues assessed puberty in 17 patients: 7 of the 12 pubertal boys (58%) had pubertal arrest, with spontaneous onset but without reaching adequate testicular volume for more than two years; FSH was raised in three, anti-Müllerian hormone near the lower limit and testosterone normal [29]. Five boys (26%) had cryptorchidism, and none had hypospadias [29]. Two sisters, with pubertal onset at 9 and 9.1 years, and one boy, with testicular volumes of 6 ml at 9.6 years, had rapidly progressive puberty and were treated with a gonadotrophin-releasing hormone (GnRH) analogue, combined with GH [29]. All three had been born small for gestational age, a condition associated with earlier or faster puberty, and the authors did not establish a causal relationship with 3M syndrome [29]. Three women in the same series had menarche at the usual age and regular cycles, and successful pregnancies have been described in women with the syndrome [29].

3.8 Heart, kidney and other organs

Aortic root dilatation has been described in two siblings [2, 16] and aortic dilatation in one patient in the Istanbul series [29]. A child with acute hydrocephalus due to haemorrhage from one of two intracranial aneurysms has been described [8]. Smith also lists, as occasional findings, intracerebral aneurysm, supernumerary nipple, diastasis recti and frequent fractures [15]. In the Saudi series there were grade 3 hydronephrosis, nephrotic-range proteinuria, nephrocalcinosis, recurrent urinary tract infections, osteopenia, deafness and a bone mineral density Z-score of −4.2 [7]. Isolated cases of Gradenigo syndrome [16], Dandy-Walker malformation [29] and, cited in the Saudi series, severe combined immunodeficiency associated with 3M syndrome [7] have been described. A patient treated with recombinant IGF-1 developed obesity, acanthosis nigricans, tonsillar hypertrophy and obstructive sleep apnoea, effects the authors attributed to the treatment [43].

3.9 Development and cognition

Development and intelligence are usually normal, and this is one of the features that distinguishes 3M syndrome from other forms of primordial dwarfism [2, 28]. In the review of 217 cases, about 20% had psychomotor delay, distributed similarly across the three genes, with normal intelligence in adulthood; intellectual disability was described only in patients with OBSL1 [14]. Hu and colleagues described early motor delay in Chinese children [44], and Smith includes mild intellectual disability among the occasional findings [15]. In the Polish family of Pasińska and colleagues, the brother had learning difficulties and the sister normal intellectual development, with independent walking after the age of two years [5].

3.10 Course through the stages of life

In the newborn and infant, the picture is easier to recognise: markedly reduced length, normal head circumference, a nose with a bulbous tip, short thorax, prominent abdomen and prominent heels [14]. In the older child, the facial features become less marked, the heels cease to be prominent in some patients, and what remains is proportionate short stature, the characteristic nose and a discreetly prominent abdomen; the tall vertebral bodies become more evident on radiography [14, 38]. In adolescence, the points of attention are male puberty, scoliosis and the aortic root [2, 29]. In adults, general health is usually good and the prognosis is good, with few complications beyond severe short stature and the orthopaedic consequences [4, 15].

4. Clinical Recognition and Warning Signs

4.1 Prenatal

Ultrasound may show short long bones and fetal growth restriction; in a Chinese report, the diagnosis was made at 24 weeks, with frontal bossing and bilateral temporal narrowing [2, 44]. These findings are not specific and usually lead to a diagnosis of intrauterine growth restriction or skeletal dysplasia, unless there is already an affected sibling or the parents are known carriers [2, 4]. The skeletal dysplasia atlas notes that prominent heels may be a clue even in the prenatal period [4]. In the Polish and Italian families, ultrasound suggested chondrodysplasia or skeletal dysplasia [5, 14], and oligohydramnios is an occasional finding [15].

4.2 Newborn and infant

3M syndrome should be considered in a term newborn with markedly reduced length (close to 40 cm), normal head circumference, no maternal or placental disease, and a nose with a bulbous tip, short thorax, prominent abdomen and prominent heels [14, 15]. Many of these newborns are initially diagnosed with achondroplasia before radiographs are taken, which led the authors of the atlas to recommend that achondroplasia should always be confirmed radiologically or molecularly [4]. Children with 3M syndrome are significantly shorter at birth than children with achondroplasia [4]. In the Polish family, the first test performed on the brother was testing for the recurrent FGFR3 variants of achondroplasia and hypochondroplasia, which was negative [5].

4.3 Child and adolescent

In a child with proportionate short stature of prenatal onset, without catch-up growth, with normal intelligence, a triangular face and radiographs showing slender long bones and tall vertebral bodies, the picture suggests 3M syndrome [2, 39]. Parental consanguinity and the presence of siblings with short stature strengthen the suspicion [2, 37]. Diagnosis may be delayed because the features become less marked with age and the radiological changes are subtle [5, 14]; the mean age at diagnosis was 2.5 years in a Tunisian series and 5.4 years in a Saudi series [7, 36]. The SGA consensus recommends referral for diagnostic work-up of SGA children with persistent short stature below −2.5 SD at 2 years or below −2 SD at 3–4 years, and considering assessment by a clinical geneticist when there is dysmorphism, malformations, microcephaly, developmental delay, intellectual disability or signs of skeletal dysplasia [17].

4.4 Warning signs

4.5 Newborn screening

There is no newborn screening for 3M syndrome.

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Clinical criteria

No consensus clinical criteria have been published [2]. GeneReviews proposes suspecting the syndrome in the presence of the combination of short stature of prenatal onset, characteristic face, musculoskeletal changes, genitourinary changes in boys, normal intelligence, suggestive radiological findings and a family history compatible with autosomal recessive inheritance, while the absence of a family history does not exclude the diagnosis [2]. The diagnosis is established in a proband with persistent growth restriction of prenatal onset and the characteristic clinical and radiological findings, and/or with biallelic pathogenic or likely pathogenic variants in CCDC8, CUL7 or OBSL1 [2]. In the Istanbul series, the clinical inclusion criterion was the combination of growth delay, characteristic dysmorphism and at least one of three musculoskeletal findings: prominent heels, slender bones or tall vertebral bodies [29].

5.2 Radiology

The radiological changes are subtle and become more evident after the age of two years [2]. The long bones are slender, with diaphyseal constriction and widened metaphyses (undermodelling), and these are the main findings; the metacarpal index, used to document the gracility of the tubular bones, is usually increased, and increased radiolucency is rare [2, 40]. The vertebral bodies are tall, with reduced anteroposterior and transverse diameters, especially in the lumbar spine; the reduction in anteroposterior diameter becomes more pronounced with age, and the age-adjusted L1 vertebral index documents the finding, with the caveat that tall vertebrae also occur in scoliosis and hypotonia [2, 34]. There may be anterior wedging of the thoracic vertebrae, irregular end plates, thoracic kyphoscoliosis and spina bifida occulta [2]. The thorax is relatively broad, with slender, horizontal ribs; the pelvic bones are small, especially the pubis and ischium, the iliac wings are flared and the obturator foramina small, although this last finding may depend on positioning [2, 15]. The femoral necks may be short [2]. Other findings include dolichocephaly, a flattened coronal suture, elbow dysplasia, short ulna, pseudoepiphyses of the second metacarpal and a prominent talus [2]. Bone age may be slightly delayed or normal [2, 44]. In the newborn, the changes are minimal: the bones, including the ribs, are somewhat gracile, and the metaphyses appear relatively broad [4, 14]. Bacchi and colleagues recommend that these changes be assessed with radiologists experienced in skeletal dysplasias, because they are subtle but have diagnostic value [14]. In Yakut patients, radiological findings are rare [14, 31].

5.3 Endocrine assessment

Endocrine assessment does not confirm the diagnosis, but it is necessary to plan treatment. The SGA consensus recommends, in the work-up of the SGA child with short stature, measurement of thyroid hormones and IGF-1, with IGFBP-3 if IGF-1 is low, and reserves the GH stimulation test for suspected deficiency [17]. In the Istanbul series, the stimulation test used clonidine and L-dopa, with complete deficiency defined as a peak below 5 ng/ml and partial deficiency as a peak between 5 and 10 ng/ml; when the peak was above 10 ng/ml, an IGF-1 generation test was performed with somatropin 0.035 mg/kg at 20:00 for four consecutive days, with measurement of IGF-1 and IGFBP-3 before and after [29]. In the series of Karacan Küçükali and colleagues, the generation test used 0.1 mg/kg/day for four days [42].

5.4 Molecular tests and algorithm

GeneReviews describes two approaches [2]. When the phenotype suggests 3M syndrome, it recommends a multigene panel including CCDC8, CUL7, OBSL1 and the genes of the differential diagnosis, which maximises detection and limits variants of uncertain significance in genes that do not explain the picture. When the phenotype is atypical and the syndrome has not been considered, it recommends exome sequencing (the most used) or genome sequencing [2]. In patients of Maghrebi, Yakut or Turkish ancestry, one may begin with targeted testing for the founder variants CUL7 c.4451_4452del, CUL7 c.4581dup and OBSL1 c.1273dup [2]. The Tunisian series, for example, sequenced only exon 24 of CUL7 and found the founder variant in all patients [36].

The resulting practical algorithm is as follows. In a child with severe growth restriction of prenatal onset, normal or relatively large head circumference and no asymmetry, non-genetic and endocrine causes are excluded and a skeletal survey is performed with lateral lumbar spine, pelvis and hand radiographs [2, 17, 39]. If there are features of Silver-Russell syndrome (asymmetry, severe feeding difficulties, prominent forehead with relative macrocephaly at birth), the first line is methylation testing of 11p15 and chromosome 7 [39, 47]. If the picture suggests 3M syndrome, the panel or founder variant testing is requested, and, if negative, exome or genome sequencing with copy number variant analysis, as a trio when possible [2, 14]. Detection of biallelic variants requires parental testing to confirm phase [2].

5.5 Performance and limitations of the tests

The clinical sensitivity of testing of the three genes has been estimated at between 80% and 90%, because of genetic heterogeneity not yet explained [34]. This estimate differs from the proportion of variants detectable by sequencing (100% of described variants), which measures the analytical performance of the method and not the fraction of patients with a molecular diagnosis [2, 34]. In the series with sequencing of the three genes, the aetiology was established in 83% of patients in the series of Simsek-Kiper and colleagues (20 of 24) and in 100% of the patients of Akalın and colleagues (25 of 25) [16, 35]. A negative test of the three genes does not exclude the syndrome in the presence of a typical clinical and radiological picture [2, 22]. DNA banking from the proband is advised when the molecular diagnosis has not been confirmed [2].

5.6 Report content and interpretation

The report should identify the gene, the reference transcript with version (NM_014780.5 for CUL7 and NM_015311.3 for OBSL1, the MANE Select transcripts), the HGVS nomenclature of both variants, zygosity, the class according to the ACMG/AMP criteria and the trans phase confirmed by parental testing [2, 6]. Two variants of uncertain significance, or one pathogenic variant and one of uncertain significance, neither establish nor exclude the diagnosis [2]. Reclassification depends on family segregation, phenotypic concordance and, for splicing variants, RNA studies; in the Italian case, an intronic variant of uncertain significance was reclassified as likely pathogenic after the patient's RNA showed skipping of exon 8 [14]. In the Istanbul series, a novel CUL7 missense variant (c.4531C>T, p.(Pro1511Ser)) remained classified as of uncertain significance, although in trans with a nonsense variant in the same gene [29]. Homozygosity without known consanguinity requires consideration of an undetected deletion or uniparental disomy [2, 22].

5.7 Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis on chorionic villi or amniotic fluid and preimplantation genetic testing are possible [2]. Without known variants, ultrasound can only suggest the diagnosis, which becomes highly probable when the parents are known carriers and the fetus has short long bones with frontal bossing [2].

6. Differential Diagnosis

6.1 Principles

Intrauterine growth restriction is a non-specific finding, present in about 0.17% of live births, and 3M syndrome must be distinguished from the other genetic syndromes and from acquired causes [2]. About 88% of low birthweight newborns show catch-up growth in the first year, and the absence of catch-up growth is more frequent when the restriction began early in pregnancy [39]. The three elements that best help to guide the diagnosis are head circumference (normal or relatively large in 3M syndrome, reduced in the microcephalic forms of primordial dwarfism), the presence or absence of body asymmetry and radiological examination of the skeleton [2, 17]. 3M syndrome belongs to group 21 of the 2023 Nosology, which brings together the forms of primordial dwarfism with slender bones [1].

6.2 Comparative table

AR, autosomal recessive; AD, autosomal dominant; LoM, loss of methylation; upd, uniparental disomy; MOPD, microcephalic osteodysplastic primordial dwarfism.

6.3 Silver-Russell syndrome

Silver-Russell syndrome shares with 3M syndrome prenatal and postnatal growth restriction, relative macrocephaly, a triangular face and, in some patients, prominent heels, which have also been described in maternal uniparental disomy of chromosome 7 [2, 39]. It is an essentially clinical diagnosis, a normal molecular test does not exclude it, and most cases are sporadic, with ICR1 hypomethylation at 11p15.5 in 35–67% and maternal uniparental disomy of chromosome 7 in 7–10% of patients according to GeneReviews [2, 47]. 3M syndrome is confirmed by the presence of biallelic variants and carries a 25% recurrence risk for siblings, which gives the distinction direct consequences for counselling [2]. The discriminating elements are limb asymmetry, frequent in Silver-Russell syndrome and absent in 3M syndrome, and the characteristic radiological findings of 3M syndrome, absent in Silver-Russell syndrome [2, 4]. Smith adds that several families with a clinical diagnosis of autosomal recessive Silver-Russell syndrome had variants in one of the 3M syndrome genes, and that the heel changes are the most useful sign for separating the two conditions [15]. Management also differs: in Silver-Russell syndrome, GH is effective and is on the label for SGA children, and the consensus emphasises feeding difficulties, hypoglycaemia, premature adrenarche and central precocious puberty [17, 47].

6.4 Mulibrey nanism

Mulibrey nanism (Perheentupa syndrome) was described in 1970 by Perheentupa and colleagues; the name is an acronym of the organs most affected, muscle, liver, brain and eye [48]. It is an autosomal recessive disease caused by variants in TRIM37 (17q22–q23), which encodes a peroxisomal protein of the ubiquitin-proteasome pathway, and it is enriched in Finland: of the more than 140 people described up to the 8th edition of Smith, 100 were Finnish [48, 52]. Orphanet records about 150 cases or families worldwide, unknown point prevalence and an annual incidence in Finland in the 1–9 per 100,000 class, with a mean value of 2.7 [53]. Growth restriction begins in the prenatal period, with mean weight and length of 2.3 kg and 45 cm at term; untreated adult height ranges from 147 to 162 cm in men and from 130 to 155 cm in women, with relatively large hands and feet, thinness in childhood and central obesity in adulthood [48]. GeneReviews notes that intrauterine restriction is usually less severe than in 3M syndrome and that the high forehead and pseudohydrocephalic cranial configuration are characteristic [2]. The face is triangular, with dolichocephaly, frontal bossing, a large fontanelle and a depressed nasal bridge; the ocular fundus shows reduced pigmentation and yellowish dots in the mid-periphery; radiology shows a J-shaped sella turcica, small or absent frontal and sphenoid sinuses and fibrous dysplasia of the long bones [34, 48]. The thick, adherent pericardium, with constrictive pericarditis, leads to congestive heart failure in half of patients, and pericardiectomy benefits about two thirds; there is hepatomegaly with haemangiomatous lesions and peliosis, renal, thyroid, ovarian and arachnoid cysts, severe insulin resistance and metabolic syndrome in adolescence, fatty liver in half of children and in all adults, and atherosclerotic changes in two thirds of adults at autopsy [48]. Menarche occurs at the usual age (median 12.5 years), but there is premature ovarian insufficiency, infertility and testicular dysgenesis [48]. The tumour risk is high: ovarian fibrothecoma in 55% and malignant tumours in 15%, including Wilms tumour (4% in Smith; less than 3% in the Oxford Desk Reference), papillary renal carcinoma, medullary and papillary thyroid carcinoma, phaeochromocytoma, ovarian carcinoma, endometrial adenocarcinoma and acute lymphoblastic leukaemia [48, 52]. GH has a modest benefit [48]. OMIM summarises the disease as a recessive growth disorder of prenatal onset with occasional progressive cardiomyopathy, failure of sexual maturation, insulin resistance with type 2 diabetes and an increased risk of Wilms tumour [54]. Echocardiography, fundoscopy and radiography of the sella turcica readily separate Mulibrey nanism from 3M syndrome, and TRIM37 sequencing confirms the diagnosis [4, 34]. The Brazilian textbook of genetic syndromes includes Mulibrey nanism in the differential of Silver-Russell syndrome, highlighting hepatomegaly, thin long bones, the sella turcica abnormality and insulin resistance [55].

6.5 IGF1R deficiency and other causes in the GH-IGF axis

IGF1R variants are an uncommon cause of intrauterine growth restriction and postnatal growth failure; heterozygotes have a height between −2.5 and −3 SD, delayed bone age and, sometimes, microcephaly and mild learning difficulties, whereas the biallelic forms are more severe, with frequent microcephaly and intellectual disability [2, 39]. The SGA consensus includes in the differential GH deficiency, Laron syndrome (GHR) and acid-labile subunit deficiency (IGFALS), with birth size less reduced than in 3M syndrome [17]. The distal 15q26 deletion, which includes IGF1R, should be sought by microarray [39].

6.6 Skeletal dysplasias and entities with tall vertebrae

The skeletal dysplasia atlas stresses that achondroplasia is excluded by the absence of the typical radiological findings (small sacrosciatic notches, decreasing interpedicular distance, short tubular bones of the hands) and that many newborns with 3M syndrome are initially labelled as having achondroplasia [4]. Kenny-Caffey syndrome differs from 3M syndrome in the face, cortical thickening, microcephaly and hypocalcaemia [49]; osteocraniostenosis has thinner tubular bones, with metaphyseal flaring and digital anomalies [50]. SOFT syndrome (short stature, onychodysplasia, facial dysmorphism, hypotrichosis; POC1A, autosomal recessive) shares the triangular face with pointed chin and short stature from birth, but has short limbs, short distal phalanges and nails, sparse hair in some patients and irregular metaphyseal ossification of the proximal femur and phalanges; 3M syndrome and the other forms of primordial dwarfism have a different face and normal metaphyseal ossification [51]. Elliott and colleagues described dolichospondylic dysplasia, with tall vertebrae and gracile tubular bones of the hands, and discussed the overlap with 3M syndrome; the 2023 Nosology incorporated this designation into CUL7-related 3M syndrome [1, 56]. Tall vertebrae, on their own, are not specific and also occur in scoliosis and hypotonia [2].

6.7 Short stature panels

In recent series of children with short stature studied by panel or exome, OBSL1 and CCDC8 variants appear among the diagnoses: a 185-gene panel in 64 Turkish children had a diagnostic yield of 28.1%, with OBSL1 among the most frequent genes [57]; exome sequencing in 51 children from consanguineous families in Iraqi Kurdistan identified a genetic cause in 61%, including CCDC8, and the authors estimated that a panel would have yielded only 10–33% [58]; in a Pakistani cohort with recessive short stature, a novel homozygous OBSL1 variant was identified [59]. These data show that 3M syndrome is also diagnosed in children studied for short stature without prior clinical suspicion.

7. Treatments and Risk Management Strategies

7.1 Organisation of care and evidence base

There are no clinical practice guidelines for 3M syndrome; the GeneReviews recommendations, revised in 2025, are based on the authors' personal experience [2]. Treatment is supportive, ideally multidisciplinary, and the dominant issues are growth and adult stature [2]. The members of the team are paediatric endocrinology (growth, puberty, gonadal function), orthopaedics (hip, spine, joint laxity), clinical genetics (diagnosis and counselling), physical and rehabilitation medicine, occupational therapy and community child health services (adapting the environment to short stature), urology (hypospadias, cryptorchidism) and, in the newborn with respiratory distress, intensive care and paediatric respiratory medicine [2, 29]. GH should be prescribed in centres with experience in growth disorders [2].

7.2 Initial assessment after diagnosis

7.3 Growth hormone: rationale

The response to somatropin (recombinant human growth hormone, rhGH) in 3M syndrome is variable: good in some patients and poor in many [2, 15]. The 2018 skeletal dysplasia atlas considered that there was no evidence to support GH as an effective treatment [4], the 2023 SGA consensus classifies the effect of GH in 3M syndrome as insufficient [17], and the 2011 review by Huber and colleagues stated that there was no specific treatment [60]. The series published after 2020 nevertheless show height gains in about half of treated patients, and GeneReviews recommends, instead of systematic abstention, a therapeutic trial of GH, particularly before puberty, with close monitoring of growth velocity and IGF-1, stopped if growth velocity decreases [2, 7, 29]. Pathophysiology explains part of the variability: cells with loss of cullin 7 have IGF-1 resistance, cells with loss of OBSL1 have combined resistance and cells with loss of CCDC8 have GH resistance [32]. In the Istanbul series, the response did not differ between CUL7 and OBSL1 and did not depend on the result of the stimulation test: among the seven responders, three had GH deficiency, two had normal GH and two had markedly raised GH [29].

3M syndrome is not a named indication for somatropin in any jurisdiction. Children with the syndrome are almost always born small for gestational age without catch-up growth, so prescription is made under the SGA indication when they meet the criteria for that indication [17, 45, 46]. The reference dose below is that of the international SGA guideline, applied by analogy, and not a dose studied specifically in 3M syndrome; the doses used in the 3M syndrome series (30 to 57 µg/kg/day) lie within the range of that guideline [17, 29, 42].

7.4 Somatropin: dose, criteria and monitoring

There are three practical differences. The guideline allows starting at 3–4 years and a dose up to 0.067 mg/kg/day, whereas the European SmPC sets the start at 4 years and the usual dose at 0.035 mg/kg/day; a dose above 0.035 mg/kg/day or a start before 4 years in the EU fall outside the conditions of the European label [17, 46]. The US labels allow starting at 2 years and do not require low growth velocity or a distance from parental height [17, 45]. The European SmPC requires discontinuation if, at the end of the first year, the growth velocity SD is below +1, a criterion that applies directly to the therapeutic trial recommended by GeneReviews for 3M syndrome [2, 46]. The European SmPC also advises against starting treatment close to the onset of puberty [46], and the 3M syndrome series suggest better results with a prepubertal start [2, 42].

Somatropin is contraindicated in acute critical illness, active neoplasia, hypersensitivity to the drug or excipients, proliferative or severe non-proliferative diabetic retinopathy and, for growth promotion, in children with closed epiphyses [45, 46]. Precautions include benign intracranial hypertension (fundoscopy before starting and in the presence of headaches, nausea or visual disturbances), slipped capital femoral epiphysis (assess any limping or hip or knee pain), progression of pre-existing scoliosis, glucose intolerance, hypothyroidism and hypoadrenalism, fluid retention and pancreatitis [45, 46]. The US label notes that some rare genetic causes of short stature increase the risk of neoplasia; there is no known increase in tumour risk in 3M syndrome, unlike the DNA repair defects, in which the SGA consensus does not recommend GH, and Mulibrey nanism [17, 45, 48]. Scoliosis and hip dysplasia, frequent in 3M syndrome, justify examination of the spine and hips before and during treatment [2, 45]. In one Saudi patient, GH was stopped because of headaches [7].

7.5 Results of growth hormone in 3M syndrome

There is no randomised or controlled trial of GH in 3M syndrome, and the evidence comes from retrospective series and case reports [7, 29]. The table summarises the available data; the definitions of response differ between studies, and the figures should not be compared across series.

These results have limitations that weigh on the decision: they are retrospective series, without a contemporaneous control group (only the Saudi series compares with untreated patients, in small numbers), with patients from different populations and genes, different response criteria and follow-up to final height in few patients [7, 29, 42]. The series of Karacan Küçükali and colleagues shows that a good initial response may not be sustained [42]. Responders cannot be distinguished at the outset by the stimulation test or by the gene [29]. In the SGA consensus, trials with 0.033 and 0.067 mg/kg/day in SGA children without an identified syndrome showed mean gains of +1.90 and +2.19 SD to (near-)final height in 56 patients, against about 0.5 SD of late growth in untreated children; these figures do not apply to 3M syndrome, in which the response is lower [17, 46]. The information to give families is that this is a therapeutic trial with an uncertain outcome, to be stopped if there is no response after one year [2, 46].

7.6 Recombinant IGF-1

Mecasermin (recombinant human IGF-1) was used in a child with 3M syndrome type 1 and evidence of GH insensitivity, before the genetic diagnosis; the child developed morbid obesity, voracious appetite, acanthosis nigricans, tonsillar hypertrophy and severe obstructive sleep apnoea, with minimal height gain, and the treatment was stopped [2, 43]. In the Polish family, the brother was treated with recombinant IGF-1 from 8 to 16 years and measured 155 cm at 18 years, with no dose data or comparison [5]. Mecasermin has no indication in 3M syndrome and is not recommended [2]; the SGA consensus reserves it for Laron syndrome, with moderate efficacy [17].

7.7 Puberty and GnRH analogues

The SGA consensus allows two years of GnRH analogue to be combined with GH when the predicted adult height at the onset of puberty is below −2.5 SD, with a mean gain of 6.6 cm in SGA children, and calls for longitudinal studies to confirm the benefit (A++) [17]. In 3M syndrome, GnRH analogues have been used in patients with rapidly progressive puberty and a fall in predicted height [29, 42]. Male pubertal arrest requires endocrine assessment, and the Istanbul authors suggest a urology consultation and discussion of fertility preservation [29]. Treatment of hypogonadism is the responsibility of endocrinology and that of hypospadias of urology [2].

7.8 Orthopaedics, surgery and rehabilitation

Hip dysplasia and dislocation, kyphoscoliosis and significant joint laxity require orthopaedic assessment and treatment, and marked laxity should lead to measures to limit the development of osteoarthritis [2]. A 2-year-old girl, referred for abnormal gait and with a homozygous loss-of-function variant in OBSL1, had severe bilateral hip dysplasia and was treated with open reduction, pelvic osteotomy, femoral shortening and a hip spica cast, first on the left and six months later on the right, with a satisfactory result at three years [30]; the authors described it as the first case, but hip dislocation had already been reported by Badina and colleagues in 2011 and appears in the Tunisian and Turkish series [29, 36, 41]. A Saudi patient had surgical correction of scoliosis [7]. Surgical limb lengthening is an option for some patients [2]. Physiotherapy, occupational therapy and community child health services provide the adaptations needed for short stature, to maximise access to the school and home environment, and assistive devices exist for people with short stature [2]. The sources consulted do not describe anaesthetic risks specific to 3M syndrome; the short thorax and the neonatal respiratory distress described in some patients are elements to consider in the pre-anaesthetic assessment [2, 37].

7.9 Regulatory status

The international non-proprietary name is somatropin; in Brazil, the package leaflet and the registration with the Brazilian Health Regulatory Agency (ANVISA) were not consulted for this article.

7.10 Recent developments and trials

Between September 2025 and October 2026 there were no clinical trials, regulatory submissions or targeted therapies for 3M syndrome: a search of ClinicalTrials.gov on 29 October 2026, by condition and by terms (3-M syndrome, 3M syndrome, CUL7, OBSL1), returned no studies on the disease, which does not prove the absence of studies in other registries. The publications of the period are observational studies: the Istanbul series on GH and puberty, published in September 2025 [29]; the Saudi series of 14 patients, from November 2025 [7]; the first Polish family, from October 2025 [5]; the Italian review of 217 cases with molecular confirmation, from December 2025 [14]; and reports and short stature cohorts with CUL7, OBSL1 or CCDC8 variants [30, 57, 59]. None of these works is a trial; all are retrospective studies or case reports, with the corresponding level of evidence.

7.11 Pregnancy, lactation and transition

Pregnancy in a woman with 3M syndrome is managed as in other forms of dwarfism or short stature, particularly to reduce the risk of preterm delivery [2], and successful pregnancies have been described [29]. The sources consulted provide no data on lactation. In the transition to adulthood, the points to maintain are orthopaedic surveillance, assessment of gonadal function and fertility in men, echocardiography with measurement of the aortic root if not performed in adolescence, and reproductive counselling [2, 29]; the SGA consensus recommends advising young adults treated with GH to adopt a healthy lifestyle and monitoring those with metabolic or cardiovascular risk factors [17].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

3M syndrome is inherited in an autosomal recessive manner [2]. The parents of a patient are, in principle, heterozygous, and molecular testing is recommended to confirm their carrier status and the phase of the variants [2]. When both are carriers, each sibling of the patient has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of inheriting neither variant [2]. Carriers are usually asymptomatic [2]. The children of an affected person are all obligate carriers, and will only be affected if the other parent is also a carrier of a pathogenic variant in the same gene; the siblings of the patient's parents have a 50% chance of being carriers [2].

8.2 Situations that alter the risk

If only one parent is a carrier and paternity and maternity are confirmed, one of the variants may have arisen de novo in the patient or in a parent with post-zygotic mosaicism, and the recurrence risk is then below 25%, although not zero [2]. Apparent homozygosity may result from a deletion of one or more exons on the other allele, not detected by sequencing, or from uniparental isodisomy of the chromosome of the carrier parent; in the latter situation, the recurrence risk is low [2]. Huber and colleagues described a patient with paternal isodisomy of chromosome 6 that included a CUL7 variant [22].

8.3 Carrier testing and cascade testing

Carrier testing in at-risk relatives requires prior identification of the familial variants [2]. It is recommended to offer testing to the reproductive partners of affected people and carriers, particularly when there is consanguinity, and to take into account the founder variants of each population: CUL7 c.4581dup in the Yakut, CUL7 c.4451_4452del in the Maghreb and OBSL1 c.1273dup in Turkey [2, 16, 31, 36]. Consanguinity was recorded in 13 of 16 Istanbul families, in 11 of 14 Saudi patients and in 4 of 7 Tunisian families [7, 29, 36]. The siblings of a patient should be assessed for short stature and, if present, for the syndrome, by molecular testing when the variants are known or by physical examination and skeletal survey when they are not [2]; the European gene card recommends testing siblings when there is consanguinity and parents for prenatal diagnosis [34]. The sources consulted do not specifically address carrier testing in minors; as the disease is apparent from birth, the assessment of a sibling with short stature is a diagnostic and not a predictive test [2], and the carrier status of an unaffected sibling has only reproductive consequences, which allows that decision to be left until the person can make it.

8.4 Prenatal and preimplantation diagnosis

The appropriate time to assess genetic risk and discuss prenatal diagnosis is before pregnancy [2]. With the familial variants identified, prenatal diagnosis and preimplantation genetic testing are possible [2]. Ultrasound may show short long bones and frontal bossing from the second trimester, findings that are non-specific but highly suggestive when the parents are known carriers [2, 44]. Opinions on the use of these tests differ between professionals and between families, and the decision is personal [2]. In cases without a molecular diagnosis, DNA banking from the proband allows future studies [2].

8.5 The adult with 3M syndrome and reproduction

Women have normal gonadal function and can become pregnant, with obstetric follow-up as in other forms of short stature to reduce the risk of preterm delivery [2, 29]. In men, gonadal dysfunction with raised FSH, reduced testicular volume and abnormal semen analysis may cause subfertility or infertility [2, 40], and fertility assessment should be part of the transition to adulthood [29].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

The prevalence of 3M syndrome is not known [2, 3]. The available figures are counts of published cases, which are not equivalent to prevalence: about 200 cases worldwide according to Orphanet and the SGA consensus, about 250 since 1975 according to GeneReviews, and about 300 according to Polish authors in 2025 [2, 3, 5, 17]. The review by Bacchi and colleagues counted 217 patients with molecular confirmation published up to March 2025 who met their inclusion criteria [14]. Al-Dosari and colleagues described 14 Saudi patients from 6 families with a homogeneous phenotype, most with a previous erroneous diagnosis of another growth restriction syndrome [8]. Several authors consider the syndrome to be underdiagnosed, because intelligence is normal, the features become less marked with age and the radiological changes are subtle [5, 7, 44].

9.2 Distribution by gene and by population

The proportions by gene depend on the population: the early European series were dominated by CUL7, the Turkish series show a high proportion of OBSL1, attributed to the founder variant c.1273dup, and the Yakut and Maghrebi isolates have a single CUL7 founder variant [31, 35, 36, 60]. None of these series measures population prevalence.

9.3 Europe, America, Portugal and Brazil

The data in the sources consulted include the molecular discovery series [21–23, 32], the series of six patients by van der Wal and colleagues [40] and, in 2025, the first Polish family and an Italian series with a literature review [5, 14]. The sources consulted do not describe series of Portuguese, Brazilian or US patients, nor frequency data for those countries. The lack of these data in the sources consulted does not demonstrate the absence of patients in these populations.

9.4 Special populations

In populations with founder variants, targeted testing for those variants is an efficient first step and allows carrier testing in consanguineous couples [2, 36]. In the Yakut, the phenotype has more neonatal respiratory complications and fewer radiological changes, which requires neonatal care and makes radiology less useful for diagnosis [14, 31]. In consanguineous families with short stature, the exome has a higher yield than panels [58].

9.5 European Reference Networks and patient associations

In Europe, 3M syndrome falls within ERN BOND, the European Reference Network for rare bone diseases (https://ernbond.eu/), because Orphanet classifies it as a rare bone disease and the Nosology includes it among the genetic skeletal disorders [1, 3, 18]. Growth management also falls within Endo-ERN, the European Reference Network for rare endocrine conditions, in the "Growth & Genetic Obesity Syndromes" thematic group (https://endo-ern.eu/) [19]. Patient and family associations include ANDO Portugal, the National Association of Skeletal Dysplasias (https://www.andoportugal.org/) [64]; Little People of America (https://www.lpaonline.org/), the MAGIC Foundation (https://magicfoundation.org/) and the Human Growth Foundation, in the USA; and the Restricted Growth Association (https://restrictedgrowth.co.uk/) and the Child Growth Foundation (https://www.childgrowthfoundation.org/), in the United Kingdom [2, 39]. The International Skeletal Dysplasia Registry of the University of California, Los Angeles registers patients with skeletal dysplasias [2].

10. Illustrative Clinical Case

10.1 Two Italian boys with 3M syndrome type 1 and evolution of the phenotype up to 12 years

Bacchi and colleagues described in 2025, in the Italian Journal of Pediatrics, two unrelated Italian boys with biallelic CUL7 variants, and followed the first from 6 months to 12 years of age [14]. The first patient was born with a length of 41 cm (−3.42 SD), a weight of 2010 g (−2.48 SD) and a head circumference of 33 cm (−1.27 SD), and there was short stature in the maternal line. At 6 months he measured 58 cm (−3.70 SD), weighed 5250 g (−3.14 SD) and had a head circumference of 43.5 cm (−0.12 SD), with appropriate psychomotor development. Examination showed relative macrocephaly, dolichocephaly and prominent forehead, short neck with prominent trapezius muscles, square shoulders, winged scapulae, pectus excavatum, short and broad thorax, hyperlordosis, prominent abdomen with diastasis recti, short limbs, prominent calcanei, hypotonia and joint laxity; the face was triangular, with a hypoplastic midface, full eyebrows, bulbous nose, long philtrum, pointed chin and prominent ears, with an appearance the authors described as melancholic (figure 1, A–E: https://pmc.ncbi.nlm.nih.gov/articles/PMC12838503/figure/Fig1/). Radiographs at birth showed slender, elongated long bones, with diaphyseal constriction and cortical thickening, tall vertebrae with reduced anteroposterior diameter and thin metacarpals and phalanges (figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC12838503/figure/Fig2/) [14].

At 2 years, the patient measured 77 cm (−2.92 SD), weighed 8150 g (−3.71 SD), had a head circumference of 50 cm (+0.96 SD) and a bone age of 9 months by the Greulich and Pyle method; the square shoulders, prominent abdomen, prominent calcanei and triangular face persisted [14]. He was lost to follow-up for about ten years, and returned to clinic at 12 years because of concern about growth. He then measured 136.3 cm (−1.76 SD), weighed 42.5 kg (+0.17 SD) and had a head circumference of 55.5 cm (+1.19 SD), with pubertal stage P3 and a testicular volume of 5 ml bilaterally; the sitting height to height ratio was 0.54 (+2.5 SD), and the familial target height was 179.5 cm. The heels were no longer prominent and the pectus had disappeared; there persisted a slightly depressed nasal bridge with an upturned bulbous tip, a slightly pointed chin, brachydactyly, a single palmar crease on the right, a discreetly prominent abdomen with diastasis recti, flat feet and distal laxity, and bone age was 9–10 years, with slightly tall lumbar vertebrae and thin long bones (figure 1, K–P; figure 2, G–K) [14]. The single nucleotide polymorphism microarray was normal; trio exome sequencing, filtered for skeletal dysplasia genes, found in CUL7 (NM_014780.5) the maternal variant c.4391A>C, p.(His1464Pro), previously described and classified as likely pathogenic, and the paternal intronic variant c.2063+5G>C, of uncertain significance. RNA analysis of peripheral blood mononuclear cells showed that the latter caused skipping of exon 8, with a premature stop codon (figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC12838503/figure/Fig3/), which allowed it to be reclassified as likely pathogenic and the diagnosis to be confirmed [14]. The article does not mention GH treatment.

The second patient, the son of first cousins, had a prenatal ultrasound suggestive of skeletal dysplasia, and invasive investigation was declined. He was born at 40 weeks weighing 2200 g (−2.18 SD), measuring 41 cm (−3.42 SD) and with a head circumference of 34 cm, Apgar 9 at the 1st and 5th minutes, and required high-flow oxygen for two days; a right inguinal hernia was diagnosed, and the babygram showed slightly slender bones and discreetly widened metaphyses in the distal femur and proximal tibia [14]. Transfontanellar ultrasound, brain magnetic resonance imaging, echocardiography, auditory evoked potentials and abdominal ultrasound were normal. At 4 months he measured 52 cm (−4.75 SD), with relative macrocephaly, a high, rounded forehead, depressed nasal bridge, bulbous nasal tip, very short thorax, very prominent abdomen, brachydactyly and prominent calcanei (figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC12838503/figure/Fig4/), and at 9 months he measured 57 cm (−5.37 SD) [14]. The exome revealed, in the homozygous state, the six-nucleotide deletion CUL7 NM_014780.5:c.1234-4_1235del p.?, which removes the splice acceptor site of exon 5, absent from gnomAD and classified as likely pathogenic [14].

10.2 Lessons from the case

The two patients illustrate what the same authors' literature review systematised: in the newborn and infant, markedly reduced length with normal head circumference, a bulbous nose, short thorax, prominent abdomen and prominent calcanei guide the diagnosis, whereas the radiological changes are subtle [14]. The course of the first patient shows the attenuation of the phenotype with age and the loss of the prominent heels, which makes diagnosis more difficult at older ages [14]. The height of −1.76 SD at 12 years, with no treatment reported, shows that the severity of the short stature varies more than the classical descriptions suggest, as the European gene card and the SGA consensus had already noted [17, 34]. Reclassification of the intronic variant by RNA analysis illustrates the value of functional assessment when the phenotype is suggestive and the molecular result is inconclusive [14]. The approach in the report is diagnostic rather than therapeutic, and the management recommendations follow section 7.

11. Prognosis and Long-Term Follow-up

11.1 Prognosis

The prognosis is good apart from the severe short stature, with relatively few complications and usually good general health [4, 15]. Untreated adult height lies between 115 and 150 cm, or 5 to 6 SD below the mean [2, 15], with a mean of −4.9 SD in eight Turkish patients who reached final height [38]. The causes of morbidity identified in the sources are respiratory distress and respiratory infections in the first year, which may be fatal, particularly in the Yakut and in some families [31, 37]; hip dysplasia and dislocation, scoliosis and joint laxity with a risk of osteoarthritis [2, 29]; male gonadal dysfunction [2, 29]; and aortic root dilatation, described in few patients [2, 29]. The effect of GH on adult height is uncertain and, in the series, occurs in about half of treated patients [29, 38].

11.2 Surveillance

The sources consulted do not define a repeat interval for echocardiography after adolescence when the first examination is normal.

12. Summary and Final Considerations

3M syndrome is an autosomal recessive primordial growth disorder caused by biallelic loss-of-function variants in CUL7 (about two thirds of cases), OBSL1 (about one third) or CCDC8 (rare), which encode the three subunits of the 3M ubiquitin ligase complex, required for microtubule dynamics, cell migration and placental development. The disease manifests as severe growth restriction from the womb, with a birth length of about 40 cm at term, normal head circumference, a triangular face with a fleshy nasal tip, short thorax, prominent abdomen and heels, slender long bones and tall vertebral bodies, and normal intelligence; adult height lies 5 to 6 standard deviations below the mean. The three forms overlap clinically, with stature on average lower in the CUL7 forms, and Yakut patients, homozygous for a CUL7 founder variant, have more neonatal respiratory complications and fewer radiological changes. Diagnosis is based on clinical and radiological suspicion and is confirmed by panel or exome, with targeted testing for the founder variants in the Maghrebi, Yakut and Turkish populations; the clinical sensitivity of testing of the three genes is 80–90%. The main differential is Silver-Russell syndrome, which is distinguished by asymmetry and the absence of the radiological findings, and has a different recurrence risk; Mulibrey nanism is distinguished by constrictive pericarditis, hepatomegaly, ocular fundus changes and tumour risk. There is no specific treatment and there are no dedicated guidelines. Somatropin, prescribed under the indication for children born small for gestational age, with the dose of the 2023 international guideline (0.033 to 0.067 mg/kg/day) and the European SmPC (0.035 mg/kg/day) as a comparison, produces gains in about half of treated patients in the published series, and should be given as a therapeutic trial in a specialised centre, stopped in the absence of a response. Surveillance focuses on growth, the hips and spine, male puberty and fertility and the aortic root, and genetic counselling follows the rules of autosomal recessive inheritance, with carrier testing and prenatal or preimplantation diagnosis when the familial variants are known.

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