Aarskog-Scott Syndrome (FGD1)

X-linked faciogenital dysplasia caused by loss of function of FGD1, a CDC42-specific guanine nucleotide exchange factor, with characteristic facies, short stature often of prenatal onset, anomalies of the hands and feet, shawl scrotum and usually mild neurodevelopmental disorders.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and clinical delineation

In 1970 Dagfinn Aarskog published in the Journal of Pediatrics the description of a familial syndrome of short stature associated with facial dysplasia and genital anomalies [14]. The entity was described as an X-linked disorder with hypertelorism, anteverted nares, a broad upper lip and a peculiar penoscrotal relationship, later called "shawl scrotum", and the affected men were fertile [1]. In 1971 Charles Scott described the same features in patients from two families with several affected males, one of them with nine males in five sibships, and emphasised ligamentous laxity, with hyperextensibility of the fingers, genu recurvatum and flat feet, as well as hypermobility of the cervical spine with an anomaly of the odontoid process and neurological deficit [1, 15]. The name "Aarskog-Scott syndrome" brings the two authors together. In 1972 Furukawa, Hall and Smith expanded the clinical description [3], and Smith continues to stress that the syndrome may be confused with Noonan syndrome [3].

In 1980 Berry and colleagues suggested that the first published description was that of Hanley and colleagues (1967), who reported siblings with multiple osteochondritis dissecans, hypertelorism, cryptorchidism, digital contractures, sternal deformity and ptosis [1]. The 2025 Turkish series revisited this hypothesis by documenting a new case of osteochondritis dissecans with molecular confirmation [16].

1.2. From clinical description to the FGD1 gene

Mapping of the locus started from a balanced X;8 translocation associated with the syndrome in a mother and her son: Tyrkus and colleagues (1980) and Bawle and colleagues (1984) described full expression in the mother, explained by preferential inactivation of the normal X [1]. Glover and colleagues (1993) placed the breakpoint at Xp11.21, between ALAS2 and DXS323 [1]. In 1994 Pasteris and colleagues isolated YAC clones spanning the breakpoint, identified a cDNA disrupted by the translocation, which they named FGD1, and showed that its variants co-segregated with the disorder; the predicted protein had 961 amino acids, homology with guanine nucleotide exchange factors (GEF) for the Rho/Rac GTPases, a cysteine-rich zinc finger-like region and two SH3-domain binding sites [8, 10]. The locus is now annotated at Xp11.22 by OMIM, HGNC and GeneReviews, and some older sources retain the designation Xp11.21 [3, 4, 8, 17].

1.3. Clinical criteria and molecular detection rate

Before the gene was cloned, Teebi and colleagues (1993) proposed primary clinical criteria (short stature, hypertelorism, short nose with anteverted nares, maxillary hypoplasia, a crease below the lower lip, mild interdigital webbing with short broad hands, short fifth finger with clinodactyly and shawl scrotum) and secondary criteria (anomalous auricles with fleshy lobes, posteriorly angulated ears, widow's peak, ptosis, downslanting palpebral fissures, joint hyperextensibility, broad feet with bulbous toes, cryptorchidism, inguinal hernia and prominent umbilicus) [18]. The first molecular series found FGD1 variants in a minority of patients with a clinical diagnosis: 8 of 46 (19.56%) in Orrico and colleagues (2004) and 11 of 60 European patients (18.33%) in Orrico and colleagues (2010) [19, 20]. Schwartz and colleagues (2000) found no variants in the probands of 25 families, including the original families of Aarskog and of Scott [8]. This discrepancy was interpreted in two ways: genetic heterogeneity or inclusion of patients with other syndromes with an overlapping phenotype, such as Noonan, Robinow or Teebi hypertelorism [11, 19]. The 2025 French series, with 111 males carrying a pathogenic variant, and the 2026 GeneReviews chapter conclude that there is no evidence of genetic heterogeneity in the syndrome as currently defined [4, 11].

In 2021 Zanetti Drumond and colleagues (authors from Minas Gerais, Brazil, and Siena, Italy) published a systematic review of 58 males with an FGD1 variant described in 22 papers and reclassified the criteria according to the observed prevalence [15]. GeneReviews notes that these criteria lack consensus and that, in current practice, diagnosis rests on identification of a pathogenic FGD1 variant [4].

1.4. Nomenclature and reclassifications

OMIM keeps "faciogenital dysplasia" (FGDY), "faciodigitogenital syndrome" and "Aarskog syndrome, X-linked" as alternative titles [1]. GeneReviews adopts the dyadic gene–phenotype nomenclature "FGD1-related faciogenital dysplasia" [4]. Two historical OMIM entries describe "Aarskog-like" families without an identified gene: 100050, with male-to-male transmission and a proposed sex-influenced autosomal dominant inheritance, and 227330, with consanguinity in Bedouin families from Kuwait and a proposed autosomal recessive inheritance [5, 6]. The Orphanet mapping groups the former under ORPHA:915 and records dominant, recessive and X-linked inheritance, whereas the recessive form has its own code, ORPHA:1974 [2, 7].

A third reclassification concerns intellectual disability. In 2002 Lebel and colleagues described three brothers with X-linked intellectual disability, short stature and small feet, without the facies, skeleton or genitalia of the syndrome, carrying a maternally inherited FGD1 missense variant (p.Pro312Leu); this family formed the basis of the entry "syndromic X-linked intellectual disability 16" (MRXS16) associated with FGD1 [8, 21]. In 2025 Chapin and colleagues re-evaluated the same family: the FGD1 variant was reclassified as benign, and methylation episignature analysis led to a novel pathogenic variant in KDM5C (p.Gly384Asp), compatible with the Claes-Jensen form [8, 22]. OMIM reclassified the variant as of uncertain significance and withdrew the phenotypic association [8]. GeneReviews states that no other germline phenotype is associated with FGD1 [4].

1.5. Definition of the entity

In this article, Aarskog-Scott syndrome refers to the faciogenital dysplasia caused by a pathogenic or likely pathogenic FGD1 variant, hemizygous in males or heterozygous in females [4]. The historical autosomal forms are treated as a nosological note and as a differential diagnosis, without an identified gene. Noonan syndrome and the RASopathies, the main differential, and Robinow syndrome, grouped with the mesomelic dysplasias, are covered here in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The FGD1 gene and its protein

The FGD1 gene is located at Xp11.22 (GRCh38 coordinates X:54,445,454–54,496,234) and the MANE Select reference transcript is NM_004463.3, which encodes the 961-amino-acid protein NP_004454.2 [8–10]. Pasteris and colleagues described more than 19 exons spanning about 100 kb; later descriptions refer to 18 coding exons [8, 23]. The murine homologue has 960 amino acids and 94.7% identity with the human protein [8]. The protein has five domains: a proline-rich region with SH3-binding sites (residues 7–330), a Dbl homology domain (DH, the catalytic RhoGEF domain), a first pleckstrin homology (PH) domain, a cysteine-rich FYVE-type zinc finger and a second, carboxy-terminal PH domain [23, 24].

2.2. Function: CDC42, the Golgi and the cytoskeleton

FGD1 is a GEF specific for the Rho GTPase CDC42: it catalyses the exchange of GDP for GTP and activates it [4, 25]. A fragment containing the DH and PH domains binds CDC42, stimulates nucleotide exchange of the isoprenylated form and activates Jun kinase (JNK) and p70 S6 kinase downstream [8]. The proline-rich amino-terminal region is necessary and sufficient for localisation to the Golgi and the plasma membrane, and the SH3-binding domain binds cortactin and the actin-binding protein mAbp1, which direct FGD1 to the subcortical actin cytoskeleton [8]. At the Golgi and in the subcortical actin network, FGD1 coordinates post-Golgi trafficking and cytoskeletal dynamics, especially in osteogenic tissues; pathogenic variants reduce CDC42 activation and disturb trafficking from the Golgi and actin–microtubule organisation, defects that in cells are partially reversed by constitutively active CDC42 or by activation of the effectors PAK1, IQGAP1, N-WASP and PAR6 [4, 26]. CDC42 activated by FGD1 takes part in RUNX2-mediated osteoblast differentiation, neuronal polarity and extracellular matrix remodelling [11, 25]. In the mouse, the kinase MLK3 acts downstream of FGD1 in bone development [3].

In bovine aortic endothelial cells, TGF-β induces tyrosine phosphorylation of Fgd1, which associates with Cdc42 and promotes podosome formation and extracellular matrix degradation; depletion of Fgd1 inhibits these processes [27]. This preclinical finding is the proposed biological basis for the aortic root dilatation and cerebral vascular dysplasias described in patients, without demonstration of causality in humans [11, 27]. In the nematode C. elegans, loss of the fgd1 homologue causes cystic dilatation of the excretory cell canals [8]. In Saudubray, FGD1 (Aarskog-Scott syndrome) appears among the disorders of vesicular trafficking in the table of neuropaediatric disorders that appear or become detectable mainly after the first year of life (Table 44.1) [28].

2.3. Disease mechanism and inheritance

The mechanism is loss of function [4]. The variants are distributed across all domains of the protein, without a hotspot, and include whole-gene deletions, which indicates that the absence of functional FGD1 in hemizygous males is sufficient to cause the phenotype [11, 23]. Smith interprets the set of missense and nonsense variants and deletions as haploinsufficiency [3].

Inheritance is X-linked; OMIM classifies it as X-linked recessive [1]. Heterozygous women are usually asymptomatic or show a partial phenotype (hands, facial features, stature), and Oxford Desk Reference describes the inheritance as "X-linked semidominant" [4, 29]. Full expression in a woman has been documented when an X;autosome translocation forced inactivation of the normal X [1]. Several case reports describe the syndrome as X-linked dominant, autosomal dominant or autosomal recessive, and two OMIM entries record families with male-to-male transmission or consanguinity [5, 6, 30–32]. In one of these families (Chinese, 10 of 29 members), FGD1 was excluded by linkage and sequencing [6]. The molecularly confirmed series show no other gene for the syndrome [4, 11]; the autosomal forms remain clinical entities without a molecular basis and may, in part, correspond to other overlapping syndromes [11].

2.4. Variant spectrum

In the French series of 111 males (79 families), 62 different variants were identified: 22 missense (35.5%), 16 frameshift (25.8%), 11 splicing (17.7%), 6 nonsense (9.7%), 6 intragenic deletions (9.7%) and one intragenic duplication (1.6%); 40 (65%) were truncating [11]. In the systematic review of 58 males, the 52 variants included 33 point variants (about 56%), 14 small deletions, 4 small insertions, 3 large deletions, 3 splicing variants and one duplication [15]. The first intragenic duplication was published in 2012 [33]. GeneReviews estimates that sequencing detects about 90% of pathogenic variants and targeted deletion/duplication analysis about 10% [4]. Deep intronic variants exist: in a family with no variant on Sanger sequencing, Aten and colleagues identified by exome a branch-point variant that caused complete skipping of exon 13 and premature termination, demonstrated in the patient's RNA [17].

The following table presents published variants with the notation normalised on the MANE transcript, verified in VariantValidator, and the historical notation where it differs.

The notation "c.934C>T" used in the 2002 paper and in OMIM is incompatible with the proline→leucine change: on the MANE transcript, c.934C>T encodes p.(Pro312Ser), and the p.(Pro312Leu) change corresponds to c.935C>T, the notation adopted by ClinVar [8, 9, 36]. Other variants were published in older nomenclatures without confirmation of the transcript, such as the 528insC insertion recurrent in two families, the nonsense p.R656X recurrent in three European families and the first splicing variant c.1935+3A>C [19, 20]. The Turkish series used NM_004463.3 and described, among others, c.1306delC p.(Leu436Cysfs*5), c.1696-1G>A, c.1815dupG p.(Thr606Aspfs*29), c.2034delA p.(Asp679Thrfs*11), c.1906C>T p.(Arg636Trp) and c.1807A>G p.(Lys603Glu), the last classified as of uncertain significance [16]. In the Danish families, c.2266dup p.(Cys756Leufs*19) and c.527dup p.(Leu177Thrfs*40) were described [37]. ClinVar listed 184 pathogenic or likely pathogenic records for FGD1 in October 2026 [36].

2.5. Genotype–phenotype correlations, expressivity and allelic disorders

No series has found a clinically relevant correlation between the type or position of the variant and the phenotype [4, 11, 15, 20]. Expressivity varies between brothers and between mother and sons [18]. In the Al-Semari family, the five males with p.(Trp447Ter) had myopathic changes and distal arthropathy, but the same finding was not reproduced as a rule in other families [15, 34]. The p.(Arg921Ter) variant, located 181 nucleotides into the last exon, is not expected to trigger nonsense-mediated decay and would give rise to a protein truncated by 40 amino acids; the corresponding family had predominant congenital joint contractures [23]. No germline allelic disorders of FGD1 have been described [4]. The association with non-syndromic X-linked intellectual disability was abandoned after the 2025 reclassification [8, 22]. In oncology, FGD1 expression is elevated in prostate and breast carcinomas and FGD1 takes part in invadopodia biogenesis; this is somatic tumour biology, unrelated to the germline disorder [8].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and the ascertainment problem

The classical description of the syndrome rests on series with a clinical diagnosis only, such as the Leuven series of 52 males [38]. Because only a minority of patients with a clinical diagnosis had an FGD1 variant, some of these series included other syndromes [11, 19]. Molecularly confirmed data come from three main sources: the systematic review of 58 males published between 2000 and 2020, with an ascertainment bias acknowledged by the authors, because patients with the features considered primary were more likely to be tested [15]; the French retrospective multicentre series of 111 males from 79 families (France, Belgium, United Kingdom and Denmark), with photographs of 88 patients reviewed by dysmorphologists and radiographs of 33 reviewed by the French reference centre for skeletal dysplasias, a mean age of 10 years at last assessment and 20 adults over 20 years of age [11]; and the Turkish series of 14 males from 13 families followed between 2000 and 2023, with detailed phenotyping and two adults diagnosed because of infertility [16]. In the French series, percentages were calculated over the patients assessable for each feature, except for heart defects and brain malformations, which were referred to the total of 111 because imaging is requested only in the presence of clinical signs [11].

3.2. Frequency of manifestations in molecularly confirmed cohorts

ADHD: attention-deficit/hyperactivity disorder.

The differences between the two columns reflect different methods: the systematic review extracted features from heterogeneous case reports, without photograph review, and did not record features such as brachymelia, swan-neck fingers or heart defects, whereas the French series used a targeted questionnaire and expert image review [11]. Ptosis appears at 58.6% in the review and 31% in the French series, and metatarsus varus at 22.4% and 72%, respectively [11, 15].

3.3. Prenatal and neonatal period

In the French series, intrauterine growth restriction (IUGR) was recorded in 45% (36/80) of pregnancies and short long bones in 59% (43/73); less frequent were clubfoot or foot malposition (11%; 9/84), facial dysmorphism, mainly hypertelorism (7%; 6/84), and hand anomalies (6%; 5/84) [11]. Two fetuses of a heterozygous woman, examined after termination of pregnancy, had IUGR, short limbs, talipes equinovarus, camptodactyly, a flat face with hypertelorism and a thick corpus callosum on ultrasound; at autopsy they showed a square face, broad forehead, hypertelorism, short nose with anteverted nares, wide mouth, thin lips, low-set ears and the rectangular thickening of the lobe from the antitragus, with no malformations other than the thick corpus callosum [11]. In the Turkish series, 6 of 11 patients with records had prenatal manifestations: short tubular bones, IUGR, polyhydramnios, talipes equinovarus, increased nuchal translucency, fetal hypokinesia, an echogenic intracardiac focus and ambiguous genitalia [16]. GeneReviews concludes that prenatal signs are frequent but non-specific outside the context of a known family history [4].

Mean gestational age at birth was 39 weeks (30–42); birth length was below the 10th centile in 60% and below the 5th centile in 45% (mean at the 16th centile), and weight and head circumference were below the 10th centile in 31% and 36% [11]. The neonatal period was usually uneventful; 14% had mild hypotonia, some had mild, transient feeding difficulties and one patient required a gastrostomy [11]. Smith describes, in historical series, marked failure to thrive in the first year with feeding difficulties and recurrent respiratory infections in 35% of patients [3].

3.4. Growth

Short stature is not constant: 72% in the French series, lower than the 83–100% of older series, which the authors attribute to ascertainment bias, because short stature was used as an inclusion criterion [11]. Height ranged from −4.1 to +1.3 standard deviations (SD); 52% of patients under 7 years (median −2.1 SD) and 33% of those over 7 years (median −1.3 SD) were below −2 SD [11]. Individual curves show acceleration of growth velocity at the end of the first decade and during puberty, and mean adult height lies at the lower limit of normal: 164 cm (−1.7 SD), ranging from 154 cm (−3.4 SD) to 172 cm (−0.4 SD) [4, 11]. On the basis of clinical series, Smith gave a final height between 160 and 170 cm, delayed bone age and late puberty [3]. Bone age was delayed in 40% (6/15) of patients with a radiograph in the French series [11]. Growth hormone (GH) deficiency was reported in 23% (10/44) of patients in the French series, without complete stimulation test data; in the earlier literature, with one exception, stimulation tests were normal [1, 11]. Oxford Desk Reference describes the short stature as rhizomelic [39], and the two Turkish adults had an arm span below their height (146 cm for 154 cm and 150 cm for 158 cm) [16].

3.5. Craniofacial features and evolution with age

The dysmorphism is present from birth [4]. All 88 French patients with a photograph had a suggestive or typical appearance, and the most frequent features were a flat face, widow's peak or upswept frontal hairline, hypertelorism, usually unilateral or asymmetric ptosis, a short nose with a broad root, anteverted nares, a long philtrum, an everted lower lip with a linear crease below it, and small, low-set, posteriorly rotated ears [11]. The series described three signs rarely mentioned before: eyebrows that are spread out and sparse laterally (68%), undulation of the upper lip on smiling (77%) and rectangular thickening of the lobe from the antitragus, present to a variable degree in 91% [11]. Facial severity varies: in a sibship with a truncating variant, one of the brothers had severe craniofacial anomalies with right hemifacial microsomia and microtia, interpreted as an extension of the phenotype or as a second disorder [8, 40]. Smith adds a rounded face and facial oedema before 4 years of age, maxillary hypoplasia and incompletely folded upper helices [3]. The French protocol, for its part, describes a face with a more triangular outline and a flat profile, a frequent frontal hair whorl, a metopic suture that is sometimes prominent in early childhood, a broad nasal root with flattening of the frontonasal angle, and folded helices; in families with several affected members, some males have features so subtle that the diagnosis would not have been considered without the family history [12]. The facial features become less marked with age: Fryns observed that post-pubertal males have only residual signs, which makes clinical diagnosis difficult in adults, and serial photographs of a Turkish patient at 3, 13 and 16 years show the same pattern [16, 38, 41].

3.6. Hands, feet and skeleton

Short broad hands (94%) with brachydactyly (81%) are almost constant; camptodactyly (56%), which mainly affects the 5th, 4th and 3rd fingers [12], predominates in young children, and swan-neck fingers (53%), with hyperextension of the proximal interphalangeal joints and limitation of the distal ones, appear with age and become more visible with the fingers extended [11]. The proximal interphalangeal joints are often broad, with redundant skin folds (68%) [11]. The feet are short and broad (71%), with metatarsus varus (72%), broad halluces (49%), short toes (43%) with bulbous tips (41%) and clubfoot (14%) [11]. Other manifestations are mild brachymelia (62%), a short broad neck (65%), pectus excavatum (37%), scoliosis (13%) and joint hyperlaxity, usually mild to moderate (37%) [11]. Osteochondritis of the knee or hip was recorded in 7 patients and multiarticular osteochondritis dissecans in 2; 4 patients had exostoses, mainly around the knees, with no functional consequence [11]. The French protocol places the frequency of osteochondritis at 5 to 10% of patients, mainly in the hips and knees, and stresses that the dissecans forms are more difficult to treat [12]. The Turkish series added a case of osteochondritis dissecans of the knee [16].

Radiographs show, almost constantly, short distal phalanges and short metacarpals, most marked in the first metacarpal; brachymesophalangy of the fifth finger (61%); cone-shaped epiphyses, mainly in the fifth finger (6 of 15 assessable); and a short broad fifth metacarpal without the usual diaphyseal narrowing (77%), sometimes broader than the fourth [11]. In the feet, the first metatarsal is broad and the distal phalanges hypoplastic in all patients with a radiograph [11]. In the axial and proximal skeleton, clavicles broad in their medial portion (82%), short broad femoral necks (89%), coxa valga (67%) and small femoral epiphyses (79%) are described [11]. Older clinical series added short tubular bones with broad metaphyses, pelvic hypoplasia and short broad first metacarpals and metatarsals [3, 38].

Vertebral anomalies were considered frequent in historical series (about one third), including hypoplasia and synostosis of cervical vertebrae and spina bifida occulta [3, 11]. In molecularly confirmed cohorts they are rare (about 4%; 2/44), usually stable and asymptomatic: hypoplasia of the posterior arch of C1 in one patient and anterior C4–C5 fusion in another, as well as a narrow lumbar canal in two adults [4, 11]. This frequency may be underestimated, because cervical radiographs were not taken in most patients [11]. Scott had already described cervical hypermobility with an odontoid anomaly and neurological deficit, and a 1983 abstract warned of the risk of spinal cord injury [1].

3.7. Genitalia, abdomen and fertility

Shawl scrotum, in which redundant scrotal skin surrounds the base of the penis, was observed in 80% of French patients, 93% (13/14) of Turkish patients and 79.3% in the systematic review; it has no clinical implications [4, 11, 15, 16]. Smith illustrates shawl scrotum in a patient with Aarskog syndrome as a minor genital anomaly, interpreted as a mild deficit in the complete migration of the labioscrotal folds, which may be accompanied by other signs of incomplete masculinisation of the external genitalia (Figure 3.8A) [42]. Cryptorchidism affects 50–70% (68% in the French series); six Turkish patients (43%) required orchidopexy and two had microrchidism [4, 11, 16]. Micropenis (11 French patients) and hypospadias (4) are less frequent [11]. The French protocol adds that cryptorchidism is often unilateral and requires surgical descent, that micropenis and hypospadias are below 10% and that shawl scrotum, although suggestive, is not pathognomonic [12]. The umbilicus has a characteristic appearance in 61%: a protruding central area surrounded by a deep ovoid depression [11]. Inguinal hernia occurs in about one third [4, 11].

Fertility is described as normal in most, and Aarskog already reported that affected men reproduced [1, 3]. The Turkish series, however, documented two adults referred for infertility: a 49-year-old man with azoospermia, three inguinal herniorrhaphies, 154 cm, submucous cleft palate, scoliosis, left microrchidism with normal FSH and LH and failure to acquire reading and writing, and a 33-year-old man with oligospermia, 158 cm, operated cryptorchidism and mild intellectual disability; oligoasthenozoospermia had previously been described in a 29-year-old man [16]. OMIM also records dolichomegasigmoid with volvulus in two young men [1]. Anal anomalies (imperforate anus, anal stenosis or severe anterior placement requiring surgery) were described for the first time in the French series, in 4 patients [11]; the French protocol, written by the same centre, counts 6 patients with anorectal malformation in its experience, states that inguinal hernias are usually recognised in the neonatal period and that umbilical hernias, less frequent, are small [12]. Renal hypoplasia and pyelectasis occurred in isolated cases in the Turkish series, and Smith mentions hypoplastic kidney and intestinal malrotation as occasional findings [3, 16].

3.8. Teeth and midface

Dental anomalies affect about 80% of patients and are undervalued: crowding (49%), late eruption and shedding (35%), malocclusion (22%), large upper central incisors (22%), taurodontism (16%), ectopic teeth (12%) and abnormal tooth shape (11%) [4, 11]. In a study of three brothers, maxillary and mandibular hypoplasia with discrepancy of the bony bases and dental agenesis led to referral to maxillofacial surgery [32]. Smith records hypodontia, late eruption, broad central incisors in the permanent dentition and a frequent need for orthodontics [3].

3.9. Eyes

Refractive errors are frequent: hypermetropia in 55%, sometimes high, and astigmatism in 61% in the French series; strabismus in 29%; asymmetric or unilateral ptosis in 31%; ophthalmoplegia in 4 patients [11]. In the Turkish series, astigmatism was found in 50% (6/12) and hypermetropia in 42% (5/12), far above the 5.2% of the systematic review, which suggests that ocular involvement is undervalued when it is not looked for [15, 16]. Smith adds amblyopia, latent nystagmus, inferior oblique overaction, blue sclerae, anisometropia, posterior embryotoxon and corneal enlargement [3].

3.10. Neurodevelopment and behaviour

Early development is usually normal, with independent walking on average at 16 months (11–28), but language is moderately delayed in almost half of patients [11]. Intellectual disability is rare and mild (16%); learning difficulties are frequent (70%) and half of the patients required special education [11]. Neuropsychological assessment of 9 patients showed a marked deficit of executive functions, with a mean full-scale intelligence quotient (IQ) of 76 (69–106) [11]. ADHD (35%) and specific learning disorders such as dyslexia, dysgraphia and dyscalculia (32%) were the most frequent comorbidities; autism spectrum disorder (ASD) and mood disorders were not reported to any significant extent [11]. The difficulties tend to improve in adulthood [4, 11]. The French protocol details the profile: language delay progresses in some patients to a specific developmental language disorder; when intellectual disability is present, verbal skills tend to exceed non-verbal ones; specific learning disorders are sometimes associated with developmental coordination disorder; the executive deficit affects planning, inhibitory control, mental flexibility and sustained attention; and about half of the children need adapted schooling, with a classroom assistant, inclusion units or, more rarely, a special education institution [12].

The figures vary with the method of ascertainment. In the Leuven series (52 males, clinical diagnosis), at least 30% had intellectual disability, two thirds of it mild, and hyperactivity and attention deficit affected 61% of the cognitively normal patients and 84% of those with a deficit, with complete regression after 12–14 years and satisfactory adult social integration [38]. In 21 boys with a clinical diagnosis assessed with standardised scales, IQ was normally distributed between 68 and 128 [43]. In the review of 58 molecularly confirmed males, developmental delay was recorded in 17.2% and ADHD in 10.3% [15]. A review of 64 studies (151 individuals) found ASD in 4.0%, autistic traits without formal assessment in 5.3%, ADHD in 10.6% and intellectual disability in 14.2%, with no study using reference instruments for ASD; the index case, an adolescent with ASD confirmed by ADOS-2 and ADI-R, had a non-verbal IQ of 115 and reduced adaptive functioning (Vineland 65) [44]. In a Dutch family with p.R402W, intellectual level ranged from normal to severe impairment and the behavioural profile included a deficit of executive attention [45].

3.11. Heart and great vessels

In the French series, 16% (18/111) had heart disease, usually benign and mainly septal defects, but only 74 patients had cardiac information [11]. Aortic root dilatation was recorded in 5 patients (4 children and one operated adult) [11]. The French protocol estimates cardiac malformations at 17–25% and dilatation of the ascending aorta at below 5%, with rare surgical cases and no aortic dissection described up to 2022 [12]. In the Turkish series, 29% (4/14) had asymptomatic cardiac anomalies, detected by screening or preoperative assessment: a small ductus arteriosus, left ventricular hypertrophy, a membranous ventricular septal defect and mild pulmonary stenosis [16]. Fernandez and colleagues (1994) described pulmonary stenosis and ventricular septal defect in 10 Japanese patients from 3 families and counted heart defects in 2 of 169 published non-Japanese cases and 2 of 20 Japanese cases [1]. Two reports document surgical aortic disease: a child with progressive aortic root dilatation and subvalvular aortic stenosis treated with root and valve replacement, and a 69-year-old man with an aortic root aneurysm, near-moderate aortic regurgitation and moderate mitral regurgitation, treated with a modified Bentall procedure, mitral repair and closure of a patent foramen ovale [46, 47]. In the Griffin family, two men had supraventricular tachycardia, with no established causal relationship [23].

3.12. Central nervous system and cerebral vessels

The brain malformations described include a thick corpus callosum (3 cases, 2 of them fetuses), ventriculomegaly (2) and gyral abnormalities [4, 11]; the French protocol also includes agenesis of the corpus callosum and points out that few patients have had brain imaging, which precludes estimating the frequency [12]. A boy with the typical syndrome and normal school performance developed generalised seizures at 9 years and had unilateral focal frontoparietal polymicrogyria [1, 35]. Cerebral vascular dysplasias are rare but have serious consequences: occipital sinus pericranii with agenesis of the lateral sinus and transosseous veins, cerebral cavernoma [11]; a dysplastic internal carotid artery, malformation or occlusion of the basilar artery and a posterior circulation aneurysm in a 13-year-old boy [30]; subarachnoid haemorrhage due to rupture of a posterior communicating artery aneurysm in a 44-year-old man [31]; spastic hemiplegia due to perinatal stroke in two unrelated men [48]; and, in a 17-year-old girl with partial expression, benign intracranial hypertension after minor trauma, a congenital scalp defect at the vertex with an underlying bone defect and absence of the straight sinus on angiography [49]. The authors of the French series consider cerebral vascular dysplasia a manifestation of the syndrome, rare but potentially fatal [11].

3.13. Muscle, skin and other findings

Myopathic symptoms, with exercise intolerance and myalgia, have been described in two adults in the French series and in published families [4, 11]. In a Saudi family, five males had symmetrical distal arthropathy with electromyographic signs of myopathy [34]. In two Danish families, three adult men had muscle changes: the most affected developed muscle fatigue and exercise intolerance at 55 years and biopsy showed COX-negative fibres, ragged blue fibres, multiple mitochondrial DNA deletions and reduced respiratory chain activity; the other two (38 and 47 years) had mildly abnormal histology without relevant symptoms, and none met the criteria for definite respiratory chain disease [37]. The most affected case was also a heterozygous carrier of a PNPLA2 variant, which may have contributed [37]. The French series acknowledges that these symptoms may result from another unidentified cause, because most patients had only targeted FGD1 analysis [11]. The Turkish series described skin changes in 36% (5/14): hyperelasticity, capillary haemangiomas, patchy hyperpigmentation, hypopigmented macules, hyperkeratotic lesions and multiple naevi [16]. OMIM records a boy with lymphoedema of the legs, and obesity in 4 of 11 patients of Orrico and colleagues (2010) [1].

3.14. Heterozygous women

The proportion of symptomatic heterozygotes has not been determined [4]. In the French series, the adult height of 54 heterozygotes averaged 159 cm (−0.75 SD; 147.5–175 cm), with 17% below −2 SD [11]. The most frequently reported findings were hand anomalies (short broad hands, swan-neck fingers, camptodactyly, partial cutaneous syndactyly) and partial facial features (hypertelorism, widow's peak, anteverted nares, thin upper lip); one had an operated atrial septal defect and seven had neurodevelopmental disorders, including three with ADHD treated with psychostimulants [11]. A Danish carrier had a widow's peak and downslanting fissures, with a normal muscle biopsy [37]. The hypothesis of skewed X inactivation to explain the variability has been raised, and full expression in a woman with an X;autosome translocation demonstrates the effect [1, 15].

3.15. Natural history and treated disease

The growth data of the French series excluded patients treated with GH from the final height figure, and therefore describe the natural history [11]. The facial attenuation, late growth acceleration and neurodevelopmental improvement in adulthood are natural history observations; there are no comparative studies showing that any intervention alters these outcomes [11, 38].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

GeneReviews proposes suspecting the diagnosis in the presence of a combination of characteristic facies (broad forehead, widow's peak, hypertelorism, short nose, anteverted nares, wide mouth and rectangular thickening of the lobes), mild to moderate short stature often of prenatal onset, skeletal anomalies (limb shortening, brachydactyly, camptodactyly, swan-neck fingers, metatarsus varus, osteochondritis, pectus excavatum, scoliosis), genital anomalies (shawl scrotum and cryptorchidism), dental anomalies, neurodevelopmental disorders of variable severity (speech delay, ADHD, executive deficit, specific learning disorders), ophthalmological changes (high hypermetropia, strabismus, ptosis) and congenital anomalies such as heart defects or cleft lip and/or palate [4]. A family history compatible with X-linked inheritance, without male-to-male transmission, strengthens the suspicion, but the absence of a family history does not exclude it [4].

Griffin and colleagues recommend considering the syndrome in boys with congenital distal joint contractures or clubfoot with an X-linked inheritance pattern or isolated occurrence, even when the craniofacial features are mild [23]. In adults, clinical diagnosis is difficult because the facies becomes less marked after puberty [16, 38].

4.2. Focused examination

In hypertelorism, the interpupillary distance is increased; it should be distinguished from telecanthus and epicanthic folds, the ocular measurements should be related to head circumference, and parallax errors avoided [50]. On genital examination, shawl scrotum points to Aarskog-Scott syndrome, a small penis to Robinow syndrome and hypospadias to Opitz syndrome [50]. Oxford Desk Reference recommends examining the parents, including ocular measurements, before counselling an apparently sporadic case [50]. Observation of the hands in extension reveals swan-neck fingers, and observation of the ear lobe, the upper lip on smiling and the eyebrows adds signs that were undervalued in older descriptions [11].

4.3. Warning and emergency signs

Some signs require immediate assessment, regardless of the syndromic diagnosis. Severe, chronic or refractory headaches, seizures, focal deficits or any sign compatible with stroke call for brain magnetic resonance imaging with angiography, because of the possibility of vascular dysplasia, aneurysm or venous malformation [4, 11, 31]. Chest pain, a new murmur or signs of aortic regurgitation in a patient with known aortic root dilatation prompt urgent cardiological reassessment [11, 47]. Neck pain, signs of spinal cord compression or neurological changes after trauma or cervical manipulation require imaging of the cervical spine [1, 4]. Ptosis that obscures the visual axis in a young child is a relative emergency because of the risk of amblyopia [4, 11]. Chronic abdominal pain in a young man may correspond to dolichomegasigmoid with a risk of volvulus [1].

4.4. Newborn screening

There is no biochemical, enzymatic or functional marker of FGD1 deficiency [24], and the sources consulted do not describe inclusion of the syndrome in newborn screening programmes.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are two published sets of clinical criteria. The Teebi criteria (1993), which predate identification of the gene, were described in section 1.3 [18]. The 2021 systematic review reclassified the features according to their prevalence in 58 males with an FGD1 variant [15]:

The authors themselves do not propose an exclusively clinical diagnosis and acknowledge ascertainment bias [15]. The French protocol reproduces this classification and notes that neither the Teebi criteria nor the reviews by Orrico (2010) and Zanetti Drumond (2021) set a minimum number of major or secondary criteria; it recommends using them with caution, mainly to assess a posteriori whether the phenotype is compatible with a variant found by high-throughput sequencing [12]. The French series showed that several features considered secondary or additional in this review (metatarsus varus, short broad hands, short neck) have a frequency above 60% when systematically sought, and that features absent from the review (rectangular thickening of the lobe, swan-neck fingers, brachymelia) are frequent [11]. The Turkish series supported moving dysplastic ears and long philtrum to primary criteria [16]. GeneReviews concludes that none of these sets has consensus and that the diagnosis is established by identification of a pathogenic FGD1 variant [4].

5.2. Establishing the diagnosis

In a male, the diagnosis is established by suggestive findings and a hemizygous pathogenic or likely pathogenic FGD1 variant; in a female, by suggestive findings, usually milder and incomplete, and a heterozygous variant [4]. Under the standards of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), pathogenic and likely pathogenic variants are both diagnostic; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [4]. The author of the GeneReviews chapter offers to review FGD1 VUS [4].

5.3. Molecular tests, in order

The ACMG (2021) and the American Academy of Pediatrics (AAP, 2025) recommend exome or genome as a first- or second-tier test in children with developmental delay, intellectual disability and/or multiple congenital anomalies [4, 51, 52]. In this context, the syndrome is often identified by "reverse phenotyping": the variant comes first and the phenotype is used to interpret it, which makes knowledge of the frequencies in section 3 relevant to classification [11]. The French protocol adds two pathway rules: larger rearrangements, which are rare, are identified by chromosomal microarray (CMA), which precedes exome or genome when the syndrome has not been considered clinically; and any FGD1 variant, whatever its class, is discussed at a clinical–laboratory interpretation meeting between molecular and clinical geneticists, with recourse to experts in the syndrome when interpretation is difficult [12]. The branch-point variant identified by Aten and colleagues was found only after relaxing the exome filters to longer intronic segments and was confirmed by skipping of exon 13 in the patient's RNA [17].

5.4. Limits of testing and interpretation

The proportion of variants detected by each method (90% and 10%) describes the distribution of variant types among patients with a confirmed diagnosis and is not the clinical sensitivity of the test in a patient with clinical suspicion [4]. In older series, the detection rate in patients with a clinical diagnosis was about 18–20%, reflecting phenotypic overlap with other syndromes [19, 20]. A negative result does not exclude deep intronic variants, complex rearrangements or mosaicism [4, 17]. Interpretation of missense variants requires caution: the p.(Pro312Leu) variant was considered causal for two decades and is now a VUS with conflicting classifications in ClinVar, after the methylation episignature revealed the actual cause in KDM5C [8, 22, 36]. A 2026 preprint describes a 2-year-old Chinese boy with speech delay, mild growth delay, delayed bone age and a neonatal atrial septal defect that closed spontaneously, without the typical facies, skeleton or genitalia, carrying the maternal variant c.16G>A p.(Ala6Thr) in FGD1, absent from population databases and not supported by in silico predictors, classified as a VUS [53]. A finding of this kind does not establish the diagnosis without segregation, a compatible phenotype or functional evidence [4].

The molecular report should state the gene, the transcript with version (NM_004463.3), the HGVS notation of the variant at the cDNA and protein levels, the zygosity (hemizygous or heterozygous), the ACMG/AMP classification with the criteria applied and, when relevant, the CNV detection technique used [4, 9]. For a VUS, segregation analysis (carrier mother, other affected or unaffected males in the family) and phenotypic reassessment guided by the known frequencies help with reclassification [4, 11].

5.5. Additional assessment after diagnosis

GeneReviews recommends the following assessments, if not already done, to establish the extent of the disease [4]:

The French series considers echocardiography mandatory at diagnosis, with examination of the aortic root [11].

The French national protocol organises the initial assessment by age and adds several details to the list above: with height below −2 SD, the paediatric endocrinology consultation assesses growth velocity, the somatotropic axis and bone age; pubertal development should be monitored so as not to miss precocious puberty, which would worsen final height; the examination looks for limited cervical mobility, and a cervical spine radiograph looking for instability is required before any general anaesthesia, but the remaining radiological work-up is not systematic without clinical signs; echocardiography at diagnosis looks for septal defects and dilatation of the ascending aorta; anorectal malformations and hernias are sought at diagnosis; brain imaging is reserved for a severe neurodevelopmental disorder, focal neurological sign, headaches or epilepsy, in which case MR angiography is discussed; the ophthalmological examination includes orthoptic assessment and cycloplegic refraction; and the initial dental assessment is carried out from 3 years of age [12]. The protocol regards the syndrome as a condition at high risk of neurodevelopmental disorder and recommends gathering information from parents, therapists and teachers, with referral to child psychiatry or paediatric neurology whenever there is doubt [12].

Source: French national protocol, initial assessment table [12].

5.6. Practical algorithm

1. Clinical suspicion (facies, short hands, shawl scrotum, short stature, metatarsus varus) or a finding on exome/genome requested for developmental delay or multiple anomalies [4, 11].
2. If the suspicion is targeted: sequencing of FGD1 or a panel including FGD1 and the differential genes; if negative, targeted deletion/duplication analysis [4].
3. If the phenotype is atypical or broad: exome or genome [4, 51].
4. Pathogenic or likely pathogenic variant: diagnosis established; test the mother; baseline assessment as in section 5.5 [4].
5. VUS: family segregation, phenotypic reassessment, possible RNA analysis or consultation with a specialist group; do not use the VUS for reproductive decisions [4, 22].
6. Negative tests with a convincing phenotype: genome and/or RNA; reconsider the differential in section 6 [4, 17].

The decision tree of the French protocol has two entry points. With clinical suspicion, targeted sequencing of FGD1 or a panel is requested, with or without MLPA and microarray; without clinical suspicion, microarray is done first and then exome or genome. All FGD1 variants found go through the clinical–laboratory interpretation meeting: a benign or likely benign variant (classes I–II) or a negative result leads to consideration of another diagnosis; a pathogenic or likely pathogenic variant (classes IV–V) confirms the syndrome; and a VUS (class III) may, after clinical correlation and segregation, be reclassified in either direction [12].

5.7. Prenatal and preimplantation diagnosis

The ultrasound signs (IUGR, short long bones, clubfoot, hypertelorism) are of low specificity, and only marked hypertelorism can be confidently anticipated on ultrasound [4, 50]. When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible [4]. In the French series, fetal diagnosis was made in two fetuses of a heterozygous woman [11].

6. Differential Diagnosis

6.1. Comparative table

AD: autosomal dominant; AR: autosomal recessive; XL: X-linked.

6.2. Noonan syndrome and the RASopathies

Noonan syndrome is the closest differential and has led to misdiagnosis since the first descriptions [3, 4]. Both combine short stature, hypertelorism, ptosis, short neck, cryptorchidism and mild learning difficulties [4]. The heart disease is a guide: dysplastic pulmonary valve stenosis and hypertrophic cardiomyopathy are typical of Noonan syndrome, whereas in Aarskog-Scott syndrome septal defects predominate and, more rarely, aortic root dilatation [4, 11]. Shawl scrotum, short hands with swan-neck fingers, metatarsus varus and rectangular thickening of the lobe favour FGD1 [4, 11]. OMIM records a patient published as Aarskog with features more suggestive of Noonan [1].

6.3. Robinow syndrome

Robinow syndrome, described in 1969 and called "fetal face syndrome", shares hypertelorism, a small upturned nose, a long philtrum, short stature, brachydactyly and genital anomalies [57]. In Smith, the picture is characterised by short stature of postnatal onset (93%), hypertelorism (100%), a small upturned nose (100%), a triangular mouth with a tented upper lip (94%), micrognathia (87%), alveolar ridge hyperplasia (66%), crowded teeth (96%), short forearms (100%), thoracic hemivertebrae (70%), rib anomalies (40%) and a small penis or clitoris with hypoplastic labia majora (94%) [57]. Smith considers the face more characteristic in Robinow syndrome than in Aarskog-Scott syndrome [57].

The recessive form (ROR2, 9q22.31; NXN, 17p13.3) is more severe, with mesomelia and acromelia, multiple costovertebral anomalies, radioulnar dislocation and hypoplasia of the proximal radius and distal ulna [57, 59, 60]. The dominant forms (WNT5A, 3p14.3; DVL1, 1p36.33; DVL3, 3q27.1) have absent or mild mesomelia; umbilical hernia (32.3%) and supernumerary teeth (10.3%) have been described only in the dominant forms, and some DVL1 variants cause osteosclerosis with deafness [54–58]. Bone Dysplasias adds a dominant form due to FZD2 (previously called dominant omodysplasia) and an X-linked form due to GPC4, and notes that ROR2 heterozygosity causes brachydactyly type B [58]. Skeletal radiographs discriminate: a distinctive metacarpophalangeal profile, bifid thumb, short broad radius and ulna with radial bowing and, in the recessive forms, vertebral segmentation anomalies [50, 58]. In Aarskog-Scott syndrome, brachymelia is mild, mesomelia is not characteristic and vertebral anomalies are rare [11]. The severe skeletal manifestations of Robinow syndrome can be seen on ultrasound from 13–14 weeks [58].

6.4. Teebi hypertelorism and syndromes with hypertelorism

Teebi hypertelorism shares the facies and has been described, in a family with a SPECC1L variant, with shawl scrotum, ptosis, abnormal umbilicus, small hands and feet and sagittal and coronal craniosynostosis; another patient, with the classical form, had a giant umbilical hernia [62]. Cleft lip and palate is much more frequent than in Aarskog-Scott syndrome, the limbs are normal and genital anomalies are uncommon [4]. Aortic root dilatation, also described in patients with SPECC1L, means that this finding cannot be used as a discriminator [11, 62]. Frontonasal dysplasia, craniofrontonasal syndrome, Opitz G/BBB syndrome, Greig syndrome, Baraitser-Winter syndrome, the ALX frontonasal dysplasias and the FREM1 or ZSWIM6 phenotypes are part of the differential diagnosis of hypertelorism; they are distinguished by craniosynostosis, facial cleft, bifid nose, polysyndactyly or brain malformation [50].

6.5. KBG syndrome

KBG syndrome shares short stature, brachydactyly and large upper central incisors, but has no shawl scrotum and is associated with seizures [4]. Large central incisors occur in 22% of patients with Aarskog-Scott syndrome, which means the features must be assessed as a whole [11].

6.6. Autosomal "Aarskog-like" forms and X-linked intellectual disability

The recessive form described in Kuwait combines overlapping facial and genital features with coarse, dry, hypopigmented hair, a long neck with sloping shoulders and absence of ptosis, in consanguineous families with affected males and females [6]. The "dominant" form rests on families with male-to-male transmission studied before molecular testing [5]. Neither has an identified gene, and the French series accepts that some of these families may correspond to other syndromes [11]. The reclassification of the Lebel family to KDM5C shows that X-linked intellectual disability with an FGD1 missense variant and without the Aarskog-Scott phenotype requires investigation of other causes [22].

6.7. Growth restriction and syndromic short stature

Prenatal growth restriction and low birth length bring the syndrome close to other causes of syndromic short stature with birth small for gestational age, such as Silver-Russell syndrome, SHORT syndrome and pseudohypoparathyroidism [3, 11]. The combination of hypertelorism, shawl scrotum, short hands with swan-neck fingers and metatarsus varus points to FGD1; body asymmetry with relative macrocephaly and fasting hypoglycaemia (Silver-Russell), Rieger anomaly with a progeroid face (SHORT) or brachydactyly of the 4th and 5th metacarpals with a rounded face, obesity and calcium–phosphate abnormalities (pseudohypoparathyroidism 1a) point to the other entities [64–66].

7. Treatments and Risk Management Strategies

7.1. Principles and evidence base

There is no therapy targeting the cause of Aarskog-Scott syndrome, nor any drug approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for this indication [4, 24]. GeneReviews states that no clinical practice guidelines have been published and that its recommendations are based on the author's experience [4]. The only formal national recommendation is the French National Diagnosis and Care Protocol (PNDS) published by the Haute Autorité de Santé in December 2022, drawn up according to the HAS method for rare diseases by a multidisciplinary group coordinated by the same author and reviewed by four reference centres; like other PNDS, it rests on literature review and expert consensus, without formal grading of the evidence [12]. The management recommendations of the French series of 111 males are the other specific source; they constitute expert opinion based on a retrospective cohort, without randomised trials [11, 24]. Management is symptomatic and multidisciplinary, coordinated by a team familiar with the syndrome [4, 11].

The French protocol defines neurodevelopmental intervention by age and by functional diagnosis, not by aetiological diagnosis [12]. Before 6 years, hypotonia or postural and motor delay, which are uncommon, justify physiotherapy or psychomotor therapy; speech and language therapy begins if the oral language deficit persists beyond 3 years, or early and more intensively when there is a cleft; any language delay requires a hearing assessment, although the syndrome does not appear to be associated with deafness; and a formal psychometric assessment is recommended at around 5 years, before entry into primary school [12]. After 6 years, most children, with mild difficulties, attend mainstream school, often with a classroom assistant; the more affected attend inclusion units or, if mainstream school is not possible, special education institutions; psychometric reassessments take place mainly in the year before each change of school stage, and follow-up continues until entry into employment [12].

In ADHD, the French protocol recommends detection and intervention as early as possible, with psychotherapy, remedial therapy and parent guidance, and leaves psychostimulants to the decision of the paediatric neurologist or child psychiatrist, always combined with non-pharmacological measures [12]; it gives no doses. NICE guideline NG87 proposes methylphenidate, short- or long-acting, as first-line pharmacological treatment from 5 years and requires a cardiology opinion before starting any ADHD medication when there is a history of congenital heart disease or cardiac surgery, a murmur, rapid regular palpitations with sudden onset and offset, or exertional syncope [67], which covers the patients with septal defects or with the supraventricular tachycardia described in one family [11, 23]. With no published dose for the syndrome, the reference is the label, by extrapolation from ADHD in general: the Portuguese SmPC of Concerta® (prolonged-release methylphenidate), indicated from 6 years, starts at 18 mg once daily, adjusts in steps of 18 mg at intervals of about one week and sets a maximum of 54 mg/day in children, with recording of blood pressure, pulse, height and weight at least every 6 months [68]; the FDA label has the same starting dose and the same maximum from 6 to 12 years and allows 72 mg/day from 13 to 17 years [69]. In this syndrome, monitoring of growth on stimulants is added to monitoring of the baseline short stature.

7.2. Growth hormone (somatropin)

7.2.1. Indication and evidence in the syndrome

GeneReviews and the French series accept somatropin in two situations: GH deficiency documented by stimulation tests, or persistent growth failure in a child born SGA without catch-up growth [4, 11]. The French series recommends determining bone age and performing a GH stimulation test when stature is below −2 SD, and starting GH cautiously in young children with mild short stature, because spontaneous improvement at the end of the first decade and at puberty may confound assessment of the response [11]. The recommendation includes alerting endocrinologists to the risk of osteochondritis [11].

The 2022 French national protocol makes these rules more explicit [12]. Height should be measured at each visit and plotted on general reference charts, because there are no syndrome-specific charts; with height below −2 SD, common causes of short stature are excluded, it is confirmed that heart disease has been looked for in the young child, and growth velocity, bone age and the somatotropic axis are determined by stimulation tests in a day hospital, because GH deficiency does not appear to be rare in this syndrome. Somatropin falls within the marketing authorisation in two situations: documented GH deficiency with height below −2 SD, at any age; and SGA birth without catch-up, from 4 years, if height remains below −2.5 SD, with treatment reimbursed in France only for height below −3 SD. Outside these situations there is no consensus; because the natural history shows catch-up after the first decade, the protocol allows waiting until 10 years to discuss GH in a child with mild short stature without complete somatotropic deficiency. The decision rests with the paediatric endocrinologist and requires informing the parents about the uncertain benefit and the risks, weighing the natural history, prior brain MRI to exclude a hypothalamic–pituitary anomaly, and close monitoring for osteochondritis [12].

The evidence of efficacy comes from observational series without a control group:

None of these studies compares treatment with natural history, and the spontaneous growth acceleration at the end of the first decade makes it impossible to attribute the improvement to the drug [11]. GeneReviews concludes that it is unclear whether GH increases height potential in this syndrome [4]. OMIM records a case of isolated GH deficiency published in 1981 [1].

7.2.2. Dose: reference guideline and labels

There is no published dose specific to Aarskog-Scott syndrome. When the indication is SGA birth without catch-up, the reference is the 2023 international consensus on SGA, drawn up by experts from ten paediatric endocrinology societies: in children born SGA with persistent short stature, somatropin at a dose of 0.033 to 0.067 mg/kg/day (maximum 0.067 mg/kg/day), starting at 0.033 mg/kg/day, with an increase within this range if the gain is below 0.5 SD in the first year (recommendation A ++), keeping serum IGF-I ≤ +2 SD, measurement of insulin-like growth factor 1 (IGF-I) at 3–6 months and then at least annually (A +++), and a recommended start in the presence of persistent short stature at 3–4 years [73]. The same consensus accepts adding two years of a gonadotrophin-releasing hormone analogue if the predicted adult height is below −2.5 SD at the onset of puberty [73]. When the indication is documented GH deficiency, the dose follows the label and the 2016 Pediatric Endocrine Society guideline on GH deficiency, idiopathic short stature and primary IGF-I deficiency [74, 75]. Use of somatropin in a child with Aarskog-Scott syndrome without GH deficiency and without SGA criteria is outside the approved indications.

Somatropin is given subcutaneously, rotating injection sites to avoid lipoatrophy [75, 76]. In the Portuguese SmPC, treatment in SGA should be stopped after the first year if the growth velocity SD is below +1, and when growth velocity is below 2 cm/year with a bone age above 16 years in boys or 14 years in girls; fasting insulin and glucose are recommended before starting and annually, an oral glucose tolerance test in patients at risk of diabetes, IGF-I before starting and twice a year, and treatment should not be started close to the onset of puberty [75]. Contraindications are growth promotion with closed epiphyses, active neoplasia and, in the FDA label, acute critical illness, hypersensitivity and proliferative or severe non-proliferative diabetic retinopathy [75, 76]. Adverse effects to monitor include benign intracranial hypertension, slipped capital femoral epiphysis and Legg-Calvé-Perthes disease, progression of scoliosis during rapid growth, oedema, arthralgia and myalgia, usually mild and in the first months [75]. In Aarskog-Scott syndrome, monitoring for osteochondritis and scoliosis is added to these effects [4, 11].

7.3. Regulatory status

7.4. Agents and circumstances to avoid; anaesthesia

Until cervical anomalies have been excluded, movements that cause sudden stress on the head and neck, such as somersaults, head-first dives and high-force cervical manipulation, should be avoided, as should cervical hyperextension during procedures [4]. A cervical spine radiograph is recommended before any general anaesthesia [4, 11]. This recommendation stands even though vertebral anomalies are rare in molecularly confirmed cohorts, because hypoplasia of the posterior arch of C1 and cervical fusions have been documented, radiographs were not systematic, and cervical hypermobility with an odontoid anomaly and neurological deficit has been described since Scott [1, 11]. Pre-anaesthetic assessment should also consider congenital heart disease and aortic root dilatation, which in the Turkish series were detected at routine preoperative assessments [11, 16]. Submucous cleft palate, described in one adult, should be looked for before airway procedures [16].

7.5. Special populations and circumstances

The sources consulted do not describe pregnancies of heterozygous women with specific complications, nor lactation data; obstetric management of a heterozygous woman follows usual practice, with prenatal diagnosis offered when the variant is known [4]. In a male fetus of a heterozygous mother, ultrasound may show IUGR, short long bones and clubfoot, findings that do not in themselves require a change in obstetric surveillance [4, 11]. In the transition to adulthood, the issues to plan for are vocational guidance in patients with learning difficulties and executive deficit, fertility assessment in men with a history of cryptorchidism, cardiological surveillance if there is aortic dilatation, and genetic information for the patients themselves and their sisters [4, 11, 16]. Fryns described satisfactory adult social integration and regression of hyperactivity symptoms after 12–14 years [38]. In adults, late-onset myopathic symptoms such as exercise intolerance justify neuromuscular assessment [37]. The French protocol provides for each paediatric specialist to refer the patient to their adult counterpart when follow-up needs to continue, ideally at a joint transition clinic; remedial, psychological and psychiatric support continues until entry into employment, in ordinary or sheltered settings, and adult autonomy may be supported by social or medico-social support services; a therapeutic education programme may also be offered to encourage participation of the patient and family and to prepare the transition [12].

7.6. Recommendations of the sources and divergences

7.7. Clinical trials and developments in 2025–2026

A search of ClinicalTrials.gov (October 2026) identified no therapeutic trials for Aarskog-Scott syndrome or for FGD1; GeneReviews refers to this registry and to the European registry, and accepts that there may be no trials [4]. The sources consulted record no marketing authorisation applications, opinions of the Committee for Medicinal Products for Human Use (CHMP) or orphan designations for this syndrome. Between November 2025 and October 2026, the developments identified were the publication of the GeneReviews chapter and a case preprint; the other 2025 milestones are listed in the table because of their relevance.

No preclinical studies with a therapeutic aim were identified. Partial rescue of the Golgi trafficking defect by constitutively active CDC42 or by CDC42 effectors has been demonstrated in cells and constitutes only a mechanistic observation [4, 26].

8. Reproductive Options and Family Counselling

8.1. Mode of transmission and recurrence risks

The syndrome is transmitted in an X-linked manner [1, 4]. The father of an affected boy is not a carrier and does not need to be tested [4]. In a family with more than one affected individual, the mother of an affected boy is an obligate heterozygote [4]. In an isolated (simplex) case, the mother may be heterozygous, the variant may have arisen de novo in the patient, or the mother may have somatic or gonadal mosaicism; about 10% of affected males have a de novo variant (11 of 111 in the French series), and molecular testing of the mother is recommended [4, 11]. Testing of leucocyte DNA may not detect somatic mosaicism and does not detect mosaicism confined to the gonads [4]. A case of maternal germline mosaicism has been documented in dizygotic male twins with the same variant, absent from the blood of a phenotypically normal mother [77]. The French protocol states that the mother is a carrier in about 90% of cases and empirically estimates the risk due to germline mosaicism at 1% when the variant is not found in the mother [12].

Fertility of affected men is usually preserved, but the oligospermia and azoospermia described in adults in the Turkish series justify semen analysis when there is a wish to have children and a history of cryptorchidism [3, 16]. Male-to-male transmission rules out the X-linked form and raises the possibility of another syndrome or of an autosomal "Aarskog-like" form [4, 5].

8.2. Testing of heterozygotes and at-risk relatives

Identification of heterozygotes requires prior knowledge of the familial variant [4]. Clinical examination of mothers and sisters (short hands, swan-neck fingers, widow's peak, hypertelorism, stature) may suggest carrier status but does not confirm it, because many heterozygotes are asymptomatic [4, 11, 50]. GeneReviews recommends clarifying the genetic status of apparently asymptomatic male relatives, older and younger, to identify early those who will benefit from echocardiography and treatment of congenital heart disease [4]. Molecular testing can also identify the relative in whom the variant arose de novo, which defines the risk for the rest of the family [4].

8.3. Prenatal diagnosis and preimplantation genetic testing

The ideal time to determine genetic risk and discuss options is before pregnancy, and counselling should be offered to young adults at risk of being carriers [4]. Once the variant has been identified in an affected relative, prenatal diagnosis and preimplantation genetic testing are possible [4]. Ultrasound alone is of limited value: the signs (IUGR, short long bones, clubfoot, hypertelorism) are non-specific and only marked hypertelorism is reliably recognisable [4, 50]. Perspectives differ among professionals and within families about the use of prenatal diagnosis in a syndrome with rare intellectual disability and usually preserved life expectancy; most professionals consider the decision a personal one [4]. The French protocol notes that, because of the usually favourable prognosis, molecular prenatal diagnosis is rarely requested; when the index case's variant is known, it can be performed by chorionic villus sampling or amniocentesis, but the admissibility of the request is decided case by case by a multidisciplinary prenatal diagnosis centre, which weighs the severity of the symptoms in the affected relative and the family's experience [12]. Preimplantation diagnosis follows the same pathway and, if accepted, is carried out in one of the five authorised centres in France (Montpellier, Paris, Nantes, Grenoble and Strasbourg); the at-risk couple should be followed before conception and during pregnancy, with psychological support and genetics and obstetrics consultations [12].

8.4. Counselling of minors and content of the consultation

Testing of asymptomatic minors has clinical justification in boys, because the diagnosis guides echocardiography and surveillance [4]. Carrier testing of girls is mainly for reproductive purposes, and GeneReviews places reproductive counselling and discussion of options in at-risk young adults [4]. The consultation should address the nature of the syndrome, the mode of transmission, the variability of expression between brothers and between mother and sons, the attenuation of features with age and the favourable neurodevelopmental course, without ignoring the rare vascular complications [4, 11, 18].

The French protocol describes the disclosure of the diagnosis as a dedicated consultation, in a private space, with time and, whenever possible, with both parents, by a doctor experienced in the syndrome; if the person who requested the test is not a geneticist, disclosure ideally takes place jointly with a geneticist or, alternatively, a genetics appointment is booked promptly [12]. The consultation explains the FGD1 result, the main features, detection of complications, the follow-up plan, medico-social aspects and genetic counselling, which may be deferred if the family does not request it at that time; a second consultation, days or weeks later, revisits the information, and a letter to the professionals caring for the child summarises what was discussed; psychological support for parents and siblings may be offered along the way [12].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The only validated population estimate is that of Orphanet: birth prevalence in Europe in the 1–9 per 1,000,000 class, with a mean value of 5 per 1,000,000, from the EUROCAT congenital anomaly registries between 2005 and 2012; worldwide point prevalence is classified as unknown [2]. This figure measures cases recognised at birth by malformation registries and depends on clinical recognition of a syndrome with subtle signs in infancy, so it tends to underestimate the true frequency [2, 24]. GeneReviews states that the true prevalence is unknown and records fewer than 200 published individuals with a confirmed variant [4]. Porteous and Goudie knew of at least 12 patients in a population of 1.6 million in the west of Scotland, a number they considered below the true figure because of underdiagnosis of a disorder with a benign course [1]. Before 2025, about 60 patients with a molecular diagnosis had been published, and the largest series had 12 patients [11, 16]. These numbers are not rates and should not be used as national prevalence. The 2022 French national protocol puts forward an estimate of 1 in 25,000, about eight times the Orphanet mean value, without stating the population, the denominator or the method, and considers the syndrome probably underdiagnosed because of the existence of mildly symptomatic forms [12]; the difference between the two figures mainly reflects the difference between cases recognised at birth by malformation registries and an expert estimate of the true frequency, and neither results from a population study with molecular confirmation.

9.2. Geographical distribution and populations studied

No founder variants of FGD1 or differences in frequency by ancestry have been described; the recurrent variants (p.R656X in three European families, c.1829G>A and c.1555C>T in two Turkish families each, 528insC in two families) have not been studied for a common haplotype [16, 19, 20]. The recessive "Aarskog-like" form was described in a Bedouin tribe in Kuwait with a common ancestor and consanguinity, which constitutes a founder-effect context for that distinct entity [6]. The Brazilian authors of the systematic review stress the usefulness of prevalence-based clinical criteria in health systems with limited access to genetic testing [15].

9.3. Special populations

In adults, diagnosis is late and may arise during the assessment of infertility or familial short stature [16]. Symptomatic heterozygous women are underdiagnosed, because their status is usually determined after the diagnosis of a male relative [11, 15]. In fetuses, diagnosis is possible only with a family history or targeted testing [4, 11].

9.4. Reference networks and patient associations

In Europe, the relevant reference network is ERN ITHACA (rare malformation syndromes and neurodevelopmental disorders), which maintains the ILIAD registry, working groups on neurodevelopmental disorders, fetal medicine and guidelines, and clinical genetics courses [13]. GeneReviews lists the Children's Craniofacial Association (ccakids.org), Face Equality International (United Kingdom; faceequalityinternational.org) and the MAGIC Foundation (magicfoundation.org), the latter dedicated to growth disorders [4]. Oxford Desk Reference gives Contact a Family (United Kingdom) and the National Organization for Rare Disorders (NORD, USA) as general resources [50]. Orphanet patient information is available at https://www.orpha.net/en/disease/detail/915 [2].

In France, the National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé, published in December 2022 and written by the "Anomalies du développement et syndromes malformatifs" reference centre of the Grand-Ouest inter-region (Tours), organises the care pathway [12]. Diagnosis, initial assessment and coordination are the responsibility of a clinical geneticist or paediatrician at an "Anomalies du développement" (CLAD) reference or competence centre of the AnDDI-Rares health filière, or at a "Déficiences intellectuelles de causes rares" centre, in liaison with the attending doctor; in children with neurodevelopmental difficulties, coordination of rehabilitation usually lies with the paediatric neurologist or child psychiatrist [12]. The attending doctor refers to the centre, supports the diagnosis and its disclosure, coordinates care, screens for complications, ensures social support and puts the family in touch with associations [12]. When a specific intervention is needed, recognition as a long-term condition (ALD), with 100% coverage, is requested, and a file is opened with the Maison départementale des personnes handicapées (MDPH) for disability-related entitlements; signs of neurodevelopmental disorder can be referred through the departmental coordination and orientation platforms, and early and school support is provided through medico-social structures (early medico-social action centres, medico-psycho-pedagogical centres and special education and home care services) [12]. There is no French patient association; the protocol refers to the English-language association The Aarskog Foundation (aarskogsyndromefoundation.co.uk), the GRANDIR association (growth disorders and growth hormone treatment) and the Xtraordinaire association (X-linked intellectual disabilities), as well as Orphanet, NORD, the AnDDI-Rares filière website, the Maladies Rares Info Services helpline and the Alliance Maladies Rares [12].

10. Illustrative Clinical Case

Griffin and colleagues (2016) described a North American family from Michigan in which the syndrome presented mainly with congenital joint contractures [23]. In the proband (individual IV-1), ultrasound at 20 weeks of gestation showed bilateral clubfoot. In early childhood, the clubfoot was corrected by the Ponseti method, with serial casting, bilateral Achilles tenotomy and corrective footwear with an abduction orthosis; difficulty opening the hands, due to flexion contractures of the fingers, was treated with splints and occupational therapy, with improved range of motion [23].

On examination, the boy had mild craniofacial features: diastema of the upper incisors, ankyloglossia, a round face, downslanting palpebral fissures with ptosis of the left eyelid, a short upturned nose with a well-formed philtrum, and small, low-set ears with overfolded helices. Ophthalmological assessment revealed bilateral hypermetropia and astigmatism; genital examination showed mild shawl scrotum and bilateral cryptorchidism, and a Still's murmur was heard. The feet had reduced plantar creases and residual metatarsus adductus (partially corrected clubfoot); the hands had a single palmar crease on the right and a transitional crease on the left, mild flexion contractures, brachydactyly and bilateral clinodactyly [23].

The family history showed an X-linked pattern over four generations: two maternal half-uncles with craniofacial dysmorphism and hand contractures, one with bilateral clubfoot and the other with a ventricular septal defect, and affected males in at least two earlier generations, two of them with supraventricular tachycardia; the adult men of known height measured about 173–175 cm (5 feet 8–9 inches) [23]. Exome sequencing of the proband and an affected uncle, with analysis focused on the X chromosome, identified in both the hemizygous variant NM_004463.3:c.2761C>T, p.(Arg921Ter), in exon 18, confirmed by Sanger sequencing; the mother and maternal grandmother were unaffected carriers [9, 23]. The variant lies in the last exon and predicts loss of the final 40 amino acids, in the second PH domain; the authors allow for the production of a truncated protein, without protein studies [23].

The open-access paper is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC4990810/; Figure 1 shows the proband's phenotype (face, bilateral metatarsus adductus and hands with contractures, brachydactyly and clinodactyly) and Figure 2 the pedigree, Sanger traces and a diagram of the protein domains with the position of p.Arg921 [23]. The case illustrates three clinical points: congenital joint contractures and clubfoot may dominate the presentation, adult stature may be normal, and the diagnosis often comes from exome sequencing; the orthopaedic management described corresponds to the conventional practice recommended by GeneReviews [4, 23]. The relationship of the supraventricular tachycardia to the syndrome was not demonstrated by the authors [23].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Life expectancy is usually preserved and most patients reach adulthood with satisfactory social integration [11, 38]. Mean adult height is 164 cm in men (−1.7 SD; 154–172 cm) and 159 cm in heterozygous women (−0.75 SD), after spontaneous growth acceleration at the end of the first decade and at puberty [11]. Learning difficulties and ADHD tend to improve in adulthood, and the facial features become less marked after puberty [11, 38]. Long-term morbidity depends on complications: orthopaedic problems (osteochondritis, scoliosis), dental and ophthalmological problems (amblyopia if ptosis or hypermetropia are not treated), infertility in some men and late myopathic symptoms [11, 16, 37]. Vascular complications are rare but determine the individual prognosis: a ruptured intracranial aneurysm at 44 years, arterial malformations and a posterior circulation aneurysm at 13 years, perinatal stroke with hemiplegia, and aortic root disease requiring surgery in childhood and at 69 years [30, 31, 46–48]. Survival to 69 years is documented [47]. The sources consulted provide no data on mortality or life expectancy. The French protocol summarises the determinants of individual prognosis as four: the severity of short stature, the presence and intensity of neurodevelopmental disorder, the existence and severity of associated malformations, and ophthalmological complications, especially amblyopia due to late-treated or untreated strabismus or ptosis [12].

11.2. Surveillance

In adults, the French protocol provides for regular visits to the family doctor, a genetics consultation at diagnosis and before a planned pregnancy (with family enquiry and molecular testing of relatives), echocardiography at diagnosis and thereafter only if there is known heart disease, dental assessment with a panoramic radiograph at diagnosis and thereafter according to the anomalies, ophthalmology as clinically indicated, and neuropsychological or psychiatric assessment in the presence of intellectual disability, ADHD or another neuropsychiatric disorder; a cervical radiograph remains mandatory before any general anaesthesia [12].

11.3. Follow-up of relatives

At-risk male relatives carrying the variant should have echocardiography and enter the same surveillance plan [4]. Heterozygous women with a partial phenotype benefit from assessment of growth, hands and neurodevelopment, and from reproductive counselling [4, 11].

12. Summary and Final Considerations

Aarskog-Scott syndrome is an X-linked faciogenital dysplasia caused by loss of function of FGD1, a GEF that activates CDC42 and coordinates Golgi trafficking and the cytoskeleton in osteogenic tissues. Since Aarskog's description in 1970 and Scott's in 1971, the picture was defined by clinical series that included other syndromes; the molecularly confirmed cohorts, in particular the French series of 111 males and the 2026 GeneReviews chapter, have redefined the syndrome. The facies (hypertelorism, rectangular thickening of the lobe, short nose with anteverted nares, widow's peak), short broad hands with swan-neck fingers, metatarsus varus and shawl scrotum are the most frequent signs; short stature often begins before birth, affects about 72% of males and tends to attenuate at the end of the first decade, with a mean adult height of 164 cm. Intellectual disability is rare and mild, but learning difficulties, executive deficit and ADHD are frequent and improve in adulthood. Cervical vertebral anomalies are rare in the molecular cohorts, and a cervical radiograph before anaesthesia remains recommended.

Diagnosis rests on identification of a pathogenic FGD1 variant (NM_004463.3), by sequencing with deletion and duplication analysis, panel or exome. The clinical criteria of Teebi and of Zanetti Drumond lack consensus. The reclassification of the p.(Pro312Leu) variant to KDM5C shows that FGD1 missense variants without a compatible phenotype require caution. The main differential includes Noonan syndrome, the Robinow syndromes, Teebi hypertelorism and KBG syndrome.

There is no treatment targeting the cause. Management is symptomatic and multidisciplinary: orthopaedics, urology, dentistry, ophthalmology, neurodevelopmental support and echocardiography at diagnosis with assessment of the aortic root. Somatropin has a place only in documented GH deficiency or in the SGA child without catch-up growth, with reference doses from the 2023 SGA consensus and the labels, and its benefit on final height has not been demonstrated. Cerebral vascular dysplasias and aortic root disease are rare but justify imaging when symptoms are present. The 2022 French national protocol adds a schedule of visits (six-monthly at the reference centre in the first two years and annually thereafter), scheduled ophthalmological examinations at 9 months, 2½ years and 6 years, dispensing with repeat echocardiograms when the initial one is normal, hypothalamic–pituitary MRI before GH and the possibility of deferring GH until 10 years in mild short stature. Genetic counselling follows the rules of X-linked inheritance, with about 10% de novo variants and documented germline mosaicism.

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