ABSTRACT
Aarskog‐Scott syndrome (AAS, MIM#305400) is an X‐linked disorder characterized by recognizable facial features, short stature, and genitourinary and skeletal malformations. AAS is attributed to pathogenic variants in FGD1, and ~60 patients with a genetic diagnosis have been reported to date. We hereby present a molecularly confirmed cohort of 14 male AAS patients from 13 families. Among 14 patients, 12 were referred during childhood, while two were referred at adulthood due to infertility. Six out of 11 patients with available records had antenatal manifestations, comprising shortened tubular bones, growth restriction, polyhydramnios, pes equinovarus, increased nuchal translucency, fetal hypokinesia, echogenic intracardiac focus, and ambiguous genitalia. In addition to well‐described AAS findings, distinctive features observed in multiple patients included variable skin findings (n = 5), renal malformations (n = 2), muscular build (n = 2), and infertility (n = 2). Cardiac (n = 4) and ocular manifestations (n = 6) were identified at significantly higher rates than previously reported. This cohort also presents new patients with osteochondritis dissecans and oligo/azoospermia, providing further evidence to acknowledge these once‐reported findings as part of the disease spectrum. Eleven different FGD1 variants, including seven novel ones, were identified through targeted FGD1 sequencing. Two variants were found to be recurrent, detected in two independent families. Our study provides additional insights into the clinical and genotypic landscape of AAS through the largest molecularly confirmed cohort, including two adult patients.
Keywords: Aarskog syndrome, Aarskog‐Scott syndrome, faciogenital dysplasia, FGD1, short stature
This study presents the deep phenotyping data of 14 new Aarskog‐Scott syndrome patients with molecular confirmation.
1. Introduction
Aarskog‐Scott syndrome (AAS, MIM#305400) is a rare developmental disorder primarily characterized by recognizable facial features, short stature, genitourinary malformations, and skeletal abnormalities [1]. However, a broad range of manifestations has been described among affected individuals, significantly complicating the AAS diagnosis on clinical grounds.
Pathogenic alterations in FGD1 (Xp11.22) have been implicated in the etiology, with ~60 causative variants reported in the Leiden open variation database [2]. FGD1 encodes a guanine nucleotide exchange factor that activates Rho GTPase Cdc42, which transmits signals involved in cytoskeletal organization, growth regulation, and embryonic morphogenesis [2]. Consequently, disruption of Cdc42 signaling due to FGD1 alterations results in various developmental abnormalities, explaining the heterogeneous clinical nature of AAS. Due to X‐linked inheritance, heterozygous females typically exhibit milder features, including mild hypertelorism, widow's peak, and brachydactyly [3].
Clinical diagnostic criteria for AAS were initially established by Teebi et al. [4]. Zanetti Drumond et al. [5] later conducted a systematic analysis of 58 reported cases, refining the previously set criteria based on observed prevalences [5]. Suggested adjustments included upgrading long philtrum, ptosis, cryptorchidism, and joint hypermobility to primary criteria; demoting short/broad hands, interdigital webbing, and camptodactyly to secondary criteria; and removing hypospadias. Moreover, a set of features was proposed to be recategorized under “additional criteria,” including metatarsus varus, crease below the lower lip, low‐set ears, round face, and ogival palatus.
Here we present the deep phenotyping data from 13 AAS families, along with molecular confirmation, to further expand the phenotypic and mutational spectrum.
2. Materials and Methods
2.1. Participants
We recruited 14 AAS patients from 13 families, diagnosed and followed in the Medical Genetics Departments at Istanbul Faculty of Medicine and Koç University School of Medicine between 2000 and 2023. Each proband underwent physical examinations by an expert clinical dysmorphologist. Written informed consent from patients/legal guardians was obtained for genetic testing and the use of photographs per local ethics protocols.
2.2. Molecular Analysis of FGD1
Genomic DNA was extracted from leukocytes using standard methods. Coding exons of FGD1 together with flanking intronic regions were amplified with PCR and Sanger‐sequenced. Genomic sequences are reported with respect to transcript NM_004463.3[GRCh38]. Pathogenicity was assessed using in silico tools (AlphaMissense, MutationTaster, Polyphen, Human Splicing Finder) and AlphaFold. Variants were categorized according to American College of Medical Genetics (ACMG) guidelines [6] and submitted to ClinVar. Familial segregation studies were performed when DNA samples were obtainable.
3. Clinical Reports
Of the 14 male AAS patients, 12 were evaluated in childhood, while two were first referred to our clinic as adults, both due to infertility. The average age at diagnosis was 9 years 7 months, with the youngest diagnosed at 21 days and the oldest at 49 years. Phenotypic data of the probands are detailed in Table 1 and shown in Figure 1.
TABLE 1.
Clinical characteristics of 14 patients with Aarskog syndrome.
| Patient number | P1 | P2 | P3 | P4 | P5 | P6 | P7 |
|---|---|---|---|---|---|---|---|
| Prenatally detected findings | N | Polyhidramnios, short femora and humeri, R PEV, mild IUGR | Short tubular bones | N | Increased NT, polyhydramnios, IUGR, PEV, EIF, fetal hypokinesia | N | IUGR, ambiguous genitalia |
| Week of gestation at birth | 36 | 36 | 41 | 40 | 35 | 40 | 38 |
| Birth weight (SD) | −0.2 | −0.34 | −0.27 | 1.38 | −1.45 | −0.05 | −1.21 |
| Birth length (SD) | 0.37 | −0.82 | −0.53 | 0.28 | NA | −0.28 | −0.8 |
| Birth OFC (SD) | NA | −1.42 | −0.99 | 0.74 | NA | −0.08 | −0.48 |
| Age at last measurement | 3 years 1 month | 21 days (CA: newborn) | 7 months | 2 years 8 months | 1 years 3 months | 16 years 3 months | 4 years 11months |
| Weight (SD) | −1.5 | −0.7 | −0.6 | −0.4 | −1.4 | −0.8 | −1.3 |
| Height (SD) | −2.6 | −1.4 | −2.9 | −0.3 | −2.4 | −1.1 | −0.6 |
| OFC (SD) | −0.7 | −1.4 | −0.8 | −0.6 | −0.5 | −2.2 | −1 |
| Short stature α, γ/short armspan | + / NA | − / + | + / − | − / + | + / + | − / + | − / + |
| Craniofacial and orodental features | |||||||
| Widow's peak β,δ | + | + | + | − | − | + | − |
| Round face ε | + | + | − | + | + | − | + |
| Frontal bossing ε | − | − | + | − | + | PF | − |
| Hypertelorism α,γ | + | + | + | + | + | + | + |
| Downward slanting palpebral fissures β,δ | − | − | − | + | − | − | − |
| Ptosis β,γ | − | − | − | + | − | − | + |
| Broad nasal bridge | + | + | + | + | + | − | + |
| Midface retrusion α,ε | + | − | − | + | + | − | − |
| Anteverted nostrils/short nose α,γ | + | + | + | − | + | + | + |
| Long philtrum β | + | + | + | + | + | + | + |
| Wide philtrum | + | − | − | − | + | − | − |
| Crease below the lower lip α,ε | − | + | − | + | − | + | − |
| Micrognathia | − | − | − | − | − | + | − |
| Abnormal auricles/posteriorly‐rotated ears/fleshy earlobes β,δ | Posteriorly rotated ears, fleshy earlobes | Overfolded helices, low‐set ears, fleshy earlobes | Fleshy earlobes, anterior helical pitting | − | − | Small ears, fleshy earlobes | Uplifted lobes, fleshy earlobes |
| Low set ears ε | − | + | − | + | − | + | + |
| Thin upper lip | + | + | + | + | − | − | − |
| Ogival palatus ε | − | + | − | − | − | + | − |
| Dental malocclusion | − | + | − | − | − | + | − |
| Skeletal findings | |||||||
| Short neck | − | + | + | − | + | − | − |
| Pectus excavatum | − | − | − | − | − | + | − |
| Cervical spine hypermobility | − | NA | NA | − | NA | − | − |
| Odontoid hypoplasia | NA | NA | NA | − | NA | − | − |
| Scoliosis | − | − | − | − | − | + | + |
| Retarded Bone Age | NA | NA | NA | − | NA | − | − |
| Hand and feet anomalies | |||||||
| Short/broad hands α,δ | + | + | + | − | + | + | − |
| Brachydactyly/wide fingers α,γ | + | + | + | + | + | + | − |
| Interdigital webbing α,δ | + | − | − | + | − | + | + |
| Camptodactyly β | − | − | − | + | − | − | − |
| Clinodactyly α,δ | − | − | − | + | − | + | − |
| Single transverse palmar crease β | − | − | + | + | + | + | + |
| Joint hypermobility β,γ | + | − | − | + | − | + | + |
| Metatarsus varus ε | + | − | − | − | + | − | − |
| Short/broad feet β,δ | + | − | − | − | + | + | − |
| Short/bulbous toes β | + | − | − | − | − | + | − |
| Genitourinary findings | |||||||
| Cryptorchidism β,γ | − | − | − | − | + | + and R microorchidism | − |
| Shawl scrotum α,γ | + | + | + | + | + | + | + |
| Hypospadias | − | − | − | − | − | − | + |
| Neurologic findings | |||||||
| Developmental delay ε | Language delay, mild | NA | − | − | Motor and language delay, mild | Language delay, mild | Motor delay, mild |
| ADHD | − | NA | NA | − | NA | + | + |
| Opthalmologic findings | |||||||
| Hyperopia | − | NA | NA | + | − | + | − (myopia) |
| Astigmatism | − | NA | NA | + | − | + | + |
| Strabismus | − | − | − | + | − | − | + |
| Connective tissue findings | |||||||
| Inguinal hernia β,δ | − | − | − | − | − | + | − |
| Umbilical hernia β,ε | − | − | − | − | − | − | − |
| Prominent umbilicus | − | + | − | + | + | + | + |
| Cardiac findings | − | − | Mild LVH | − | VSD | PS, small PDA | Small PDA |
| Other findings | − | − | − | − | Mild renal pelviectasis | 2 accessory hairwhorls, ankyloglossia, osteochondritis dissecans (L knee), muscular build, pes planus, osteopenia | Patchy hyperpigmentation, frequent infections, pes planus, sacral dimple, hydrocele, chronic constipation |
| FGD1 variant | c.1328G>A | c.1306delC | c.1696‐1G>A | c.1829G>A | c.1555C>T | c.1815dupG | c.1807A>G |
| Inheritance | Maternal | de novo | Maternal | Maternal | Maternal | de novo | NA |
| Maternal findings | Widow's peak | − | N | Mild interdigital webbing | N | − | NA |
| Patient number | P8 | P9 | P10 | P11 | P12 | P13 | P14 |
|---|---|---|---|---|---|---|---|
| Prenatally detected findings | Short femora | NA | N | Short tubular bones | N | NA | NA |
| Week of gestation at birth | 40 | 40 | 40 | 39 | 40 | NA | NA |
| Birth weight (SD) | −0.98 | NA | 0.7 | 0 | −3.88 | NA | NA |
| Birth length (SD) | −2.41 | NA | NA | −2.55 | −2.91 | NA | NA |
| Birth OFC (SD) | −1.68 | NA | NA | NA | NA | NA | NA |
| Age at last measurement | 12 years 5 months | 6 years | 9 years 8 months | 13 years 10 months | 13 years 1 month | 49 years | 33 years |
| Weight (SD) | −1.8 | 0.4 | −0.4 | −2.6 | −0.6 | −0.9 | −0.2 |
| Height (SD) | −2.1 | 0.2 | −0.9 | −2.5 | −2.3 | −3.6 | −3 |
| OFC (SD) | −2.6 | −1.2 | −2 | −2.2 | −2.2 | −3.1 | −1.1 |
| Short stature α, γ/short armspan | + / NA | − / NA | − / NA | + / NA | + / NA | + / + | + / + |
| Craniofacial and orodental features | |||||||
| Widow's peak β,δ | + | − | + | + | − | + | + |
| Round face ε | + | − | − | − | − | − | − |
| Frontal bossing ε | − | − | + | − | − | PF | PF |
| Hypertelorism α,γ | + | + | + | + | + | + | + |
| Downward slanting palpebral fissures β,δ | − | − | + | − | + | − | − |
| Ptosis β,γ | − | − | + | + | + | − | − |
| Broad nasal bridge | + | + | + | + | + | − | − |
| Midface retrusion α,ε | − | + | + | + | − | + | + |
| Anteverted nostrils/short nose α,γ | + | + | + | + | + | + | + |
| Long philtrum β | − | + | + | − | − | + | − |
| Wide philtrum | − | − | − | − | + | − | + |
| Crease below the lower lip α,ε | + | + | + | − | + | − | + |
| Micrognathia | − | − | + | − | − | − | − |
| Abnormal auricles/posteriorly‐rotated ears/fleshy earlobes β,δ | Underfolded helices, posteriorly rotated | − | Underfolded helices | − | Underfolded helices | Question mark ears (mild), fleshy earlobes | Underfolded helices, posteriorly rotated ears, fleshy earlobes |
| Low set ears ε | − | − | + | + | + | + | + |
| Thin upper lip | − | − | + | − | − | + | + |
| Ogival palatus ε | + | − | − | + | − | + | + |
| Dental malocclusion | + | − | ‐ (wide upper central incisors) | + | ‐ (hypodontia) | ‐ (multiple cavities) | + |
| Skeletal findings | |||||||
| Short neck | + | + | − | − | + & webbed | − | + |
| Pectus excavatum | − | + | + | + | + | + | − |
| Cervical spine hypermobility | − | − | + | − | − | − | − |
| Odontoid hypoplasia | C1 hypoplasia | − | NA | NA | NA | − | − |
| Scoliosis | − | − | − | − | − | + | − |
| Retarded Bone Age | + | + | + | − | NA | NA | NA |
| Hand and feet anomalies | |||||||
| Short/broad hands α,δ | + | + | − | − | − | + | + |
| Brachydactyly/wide fingers α,γ | + | + | + | + | + | + | + |
| Interdigital webbing α,δ | + | + | + | + | + | − | − |
| Camptodactyly β | − | − | − | + | − | − | − |
| Clinodactyly α,δ | + | + | + | + | − | − | + |
| Single transverse palmar crease β | + | + | − | − | − | − | − |
| Joint hypermobility β,γ | + | + | + | − | − | − | + |
| Metatarsus varus ε | − | − | − | − | − | − | − |
| Short/broad feet β,δ | − | − | − | − | − | + | − |
| Short/bulbous toes β | − | − | + | − | − | + | − |
| Genitourinary findings | |||||||
| Cryptorchidism β,γ | + | + | − | + | − | − (L microorchidism) | + |
| Shawl scrotum α,γ | + | − | + & bifid | + | + | + | + |
| Hypospadias | − | − | − | − | − | − | − |
| Neurologic findings | |||||||
| Developmental delay ε | − | − | Language delay and ID, mild | − | − | − | ID, mild |
| ADHD | − | − | + | − | − | − | − |
| Opthalmologic findings | |||||||
| Hyperopia | + | + | + | − | − | − | − |
| Astigmatism | + | + | + | − | − | − | − |
| Strabismus | − | − | − | − | − | − | − |
| Connective tissue findings | |||||||
| Inguinal hernia β,δ | − | − | + | − | − | + | + |
| Umbilical hernia β,ε | − | − | − | − | − | − | − |
| Prominent umbilicus | + | − | − | − | − | − | − |
| Cardiac findings | − | − | − | − | − | − | − |
| Other findings | Large corneas, gingival hypertrophy, delayed anterior fontanel closure | Large corneas, hyperelastic skin | R corectopia, 2 accessory nipples, inverted nipples, hyperkeratotic skin lesions, gynecomastia | Mild renal hypoplasia, capillary‐cutanous hemangioma (neck), hypopigmented spots, muscular build, cubitus valgus | Upsweep hair, multiple nevi, cubitus valgus | Submucosal cleft palate, sensorineural hearing loss (paternal), infertility (azoospermia), sparse scalp/body hair and eyebrows | Infertility (oligospermia) |
| FGD1 variant | c.1555C>T | c.1555C>T | c.2034delA | c.527dup | c.1906C>T | c.1341G>A | c.1829G>A |
| Inheritance | Maternal | Maternal | Maternal | Maternal | NA (pedigree supports maternal inheritance) | NA | NA |
| Maternal findings | Short stature (153 cm) | Short stature (153 cm) | Short stature (146 cm), dysplastic ears, clinodactyly, mild brachydactyly | Widow's peak, mild hypertelorism, anteverted nares, mild brachydactyly | N | NA | NA |
Note: α, primary diagnostic criterion, established by Teebi et al. β, secondary diagnostic criterion, established by Teebi et al. γ primary diagnostic criterion, revised by Drumond et al. δ secondary diagnostic criterion, revised by Drumond et al. ε additional diagnostic criterion, revised by Drumond et al.
Abbreviations: CA, corrected age; EIF, echogenic intracardiac focus; ID, intellectual disability; IUGR, intrauterine growth restriction; L, left; LVH, left ventricular hypertrophy; N, normal; NA, not applicable; NT, nuchal translucency; PDA, patent ductus arteriosus; PEV, pes equinovarus; PF, prominent forehead; PS, pulmonary stenosis; R, right; SD, standard deviations; VSD, ventricular septal defect.
FIGURE 1.
Clinical images of the patients and the identified FGD1 variants. (A‐D) shows pediatric patients with AAS. (A) corresponds to P1 at 3 years, while (B–D) illustrate the evolving phenotype of P6, photographed at 3 years (B), 13 years (C), and 16 years 3 months (D). (E–G) presents adult patients. Note that the overall facial gestalt is more recognizable in prepubertal patients, and follow‐up of P6 (B–D) demonstrated that dysmorphic features became less apparent over time. Hand photographs of P6 taken 10 years apart (H, I) revealed a similar pattern, with brachydactyly and interdigital webbing more pronounced in early childhood. Additional findings include non‐fixed swan‐neck deformity of the fingers (J), gynecomastia, pectus excavatum (K), and uplifted earlobes (L). Schematic diagram of the FGD1 protein (M) showing the variants identified in this study. Novel variants are depicted in bold, while recurrent variants are marked with an asterisk (*).
4. Results and Discussion
4.1. Clinical Observations
4.1.1. Pre‐ and Perinatal Features
Antenatal findings were reported in 55% (n = 6/11) of the patients with available records. Anomalies observed in multiple fetuses included shortened tubular bones, intrauterine growth restriction, pes equinovarus, and polyhydramnios, reported in 36% (n = 4/11), 27% (n = 3/11), 18% (n = 2/11), and 18% (n = 2/11) of the patients, respectively. Regarding the tubular bone shortening, two displayed rhizomelia, while two had shortening of all bones. Three patients were born late preterm (n = 3/12, 25%), while the remaining (n = 9/12, 75%) were born at term. Most patients (n = 11/12, 92%) had a birth weight appropriate for gestational age, while one (8%) had low birth weight. Of those with available data, 67% (n = 6/9) had normal birth length, and 33% (n = 3/9) had short stature (−2 to −3 SD). All patients with recorded head circumference measurements were within normal range (n = 6/6).
4.1.2. Facial Phenotype
The most frequent facial features were hypertelorism (n = 14/14, 100%), anteverted nostrils/short nose (n = 13/14, 93%), dysplastic ears (n = 12/14, 86%), broad nasal bridge (n = 11/14, 79%), and long philtrum (n = 10/14, 71%).
Dysplastic ears and long philtrum have been suggested to be moved from secondary to primary criteria in the proposed revisions [5], and their high frequency in this study supports that these features should rightfully be listed as primary criteria.
4.1.3. Hand and Foot Anomalies
Common acral findings included brachydactyly (93%, n = 13/14), short/broad hands (64%, n = 9/14), interdigital webbing (n = 9/14, 64%), and joint hypermobility (57%, n = 8/14). Camptodactyly was identified in 14% (n = 2) and responded well to conservative management.
The frequency data on acral findings in the literature show inconsistencies. The study that established the initial criteria [4] reported mild webbing in 70% of patients, while the later review found a prevalence of 35% [5]. Considering the lower rate, interdigital webbing was demoted from primary to secondary criterion in the revised version. However, the latter study provided separate rates for syndactyly (24%) and webbing (35%), suggesting that separating these categories may have led to discordant results. Therefore, we propose reconsidering this finding as a primary criterion.
4.1.4. Musculoskeletal Findings
Short stature was evident in 50% (n = 6/12) of the pediatric patients, with all having heights between −2 and −3 SD. The two adult patients exhibited more pronounced short stature, with one at −3 SD and the other at −3.6 SD. Among patients ≥ 10 years, 83% (n = 5/6) were below −2 SD for height, compared to 38% (n = 3/8) of those younger than 10 years. This data supports the notion of a later onset and progression of short stature as patients age.
Osteochondritis dissecans of the knee was observed in one patient. Notably, a clinical report from 1967 [7] documented two brothers with osteochondritis dissecans. They also exhibited hypertelorism, ptosis, cryptorchidism, brachydactyly, camptodactyly, and partial syndactyly. This constellation of features strongly resembles AAS, suggesting that this report may represent the earliest AAS documentation and raises the possibility that osteochondritis dissecans is a rare manifestation of this disorder.
Constitutional muscular build was observed in two unrelated probands. Conditions potentially associated with muscular hypertrophy, such as myostatin alterations, were not ruled out at the genomic level in those cases; thus, establishing a firm association necessitates further clinical reports.
4.1.5. Ophthalmological Findings
Refractive errors were frequently encountered in the form of astigmatism (n = 6/12, 50%) and hyperopia (n = 5/12, 42%). In the literature, astigmatism is reported as the most common ocular manifestation, with a prevalence of only 5.2% [5], suggesting that ophthalmological involvement may often be overlooked.
4.1.6. Genitourinary Findings
Shawl scrotum was observed in 93% (n = 13/14) of the cohort. Six patients (43%) required orchiopexy, two (14%) had microorchidism, and one was operated on for glandular hypospadias with hydrocele. Renal hypoplasia and pelviectasis were detected in single cases.
4.1.7. Neurological and Psychiatric Features
Mild language and gross motor delays were reported in four (29%) and two cases (14%), respectively, with three of them later receiving a diagnosis of attention deficit and hyperactivity disorder. Mild intellectual disability was evident in two cases (14%).
4.1.8. Cardiac Findings
Congenital heart defects have been rarely reported in AAS but span a broad spectrum, including atrial septal defect, ventricular septal defect (VSD), pulmonary stenosis (PS), patent ductus arteriosus (PDA), patent foramen ovale, and aortic root aneurysm [3, 8, 9, 10].
We observed cardiac anomalies at a notably higher rate of 29% (n = 4/14) of our cohort, including small PDA, left ventricular hypertrophy, membraneous VSD, and mild PS. Of note, none of these anomalies had apparent clinical manifestations and all were detected either through referral for AAS or routine preoperative evaluation. One explanation for these contrasting rates may be the lack of comprehensive cardiac evaluation in cases with no or subtle symptoms.
4.1.9. Skin Findings
Apart from individual cases with hyperelasticity [11], cutaneous hemangioma [8], and atopic dermatitis [12], skin involvement has not been recognized as part of the syndrome's phenotypic spectrum. Nevertheless, variable skin findings (n = 5/14, 36%), including hyperelasticity, capillary‐cutaneous hemangiomas, patchy hyperpigmentation, hypopigmented spots, hyperkeratotic lesions, and multiple nevi observed in our cohort indicate wide variability in the dermatological manifestations of AAS.
4.1.10. Adult Patients
Since AAS is typically diagnosed during childhood, descriptions of adult males remain rare in the literature [1, 10, 13, 14, 15, 16]. Two patients (P13–P14) reported herein, who were diagnosed with AAS in adulthood, initially sought consultation due to infertility.
P13, a 49‐year‐old man, presented with azoospermia and a history of three inguinal hernia surgeries. He exhibited disproportionate short stature (height: 154 cm, armspan: 146 cm), dysmorphic features, submucosal cleft palate, scoliosis, short hands, brachydactyly, sparse facial and body hair, shawl scrotum, and left microorchidism with normal FSH/LH levels. He never acquired reading/writing skills and worked in basic jobs. His brother was 154 cm tall, and his relatively short sister (155 cm) had fertility issues.
P14 was referred due to oligospermia at 33 years of age. His medical history included inguinal hernia and cryptorchidism operations. He had rhizomelic short stature (height: 158 cm, armspan: 150 cm), dysmorphic features, short hands, brachydactyly, digital hypermobility, shawl scrotum, and mild intellectual disability.
Chromosome analyses revealed a normal male karyotype in P13 and 45,XY,rob(13;14)(q10;q10) in P14, potentially explaining the abnormal semen parameters. FGD1 sequencing confirmed AAS in both patients.
Late pubertal development, as observed in P13, was documented in several AAS patients, and fertility is generally considered normal despite the delay. Nevertheless, oligoasthenozoospermia has been reported at least once in a 29‐year‐old AAS patient [1]. Altogether, these data indicate that infertility may be a potential AAS manifestation.
Recent reports have suggested that myopathy may be a late‐onset presentation in AAS [14, 16]. However, as neither patient reported muscle weakness, muscle/joint pain, or exercise intolerance, nor had any signs on physical examination, muscle biopsy was not performed. Regular follow‐ups were recommended to monitor potential myopathic involvement.
4.2. Molecular Data and Maternal Evaluations
We identified 11 different FGD1 variants across 13 families (Table 2). All except one were class 4/5 variants based on the ACMG criteria, with the remaining one being a VUS. AlphaMissense classified the latter as likely pathogenic (0.9995) and AlphaFold predicted altered tertiary protein structure (File S1). Variants were distributed along the gene, with a greater concentration within the DH and PH1 domains (Figure 1). Seven variants have not been previously reported in affected individuals. Two variants were identified in independent families.
TABLE 2.
Molecular summary of the FGD1 variants identified in this study.
| Patient no | Nucleotide | Protein | Location on gene | Location on domain | Allele frequency (gnomAD) | ACMG | Reference |
|---|---|---|---|---|---|---|---|
| P1 | c.1328G>A | p.(Arg443His) | Exon 6 | DH | — | Likely Pathogenic | Orrico et al. (2004) |
| P2 | c.1306delC | p.(Leu436Cysfs*5) | Exon 6 | DH | — | Likely Pathogenic | — |
| P3 | c.1696‐1G>A | p.? | Intron 9 | — | — | Likely Pathogenic | — |
| P4 | c.1829G>A | p.Arg610Gln | Exon 10 | PH1 | — | Likely Pathogenic | Orrico et al. (2000) |
| P5 | c.1555C>T | p.Arg519Cys | Exon 8 | DH | — | Likely Pathogenic | — |
| P6 | c.1815dupG | p.Thr606Aspfs*29 | Exon 10 | PH1 | — | Likely Pathogenic | — |
| P7 | c.1807A>G | p.Lys603Glu | Exon 10 | PH1 | — | Variant of Uncertain Significance | — |
| P8&P9 sibship | c.1555C>T | p.Arg519Cys | Exon 8 | DH | — | Likely Pathogenic | — |
| P10 | c.2034delA | p.Asp679Thrfs*11 | Exon 13 | — | — | Likely Pathogenic | — |
| P11 | c.527dup | p.Leu177fs*40 | Exon 3 | PRD | — | Likely Pathogenic | Orrico et al. (2004) |
| P12 | c.1906C>T | p.Arg636Trp | Exon 11 | PH1 | — | Likely Pathogenic | — |
| P13 | c.1341G>A | p.Trp447* | Exon 7 | DH | — | Pathogenic | Al‐Semari et al. (2013) |
| P14 | c.1829G>A | p.Arg610Gln | Exon 10 | PH1 | — | Likely Pathogenic | Orrico et al. (2000) |
Familial segregation was performed in nine families, revealing that the causative alterations occurred de novo in two probands and were inherited in seven. Of the seven heterozygous mothers, two did not exhibit any clinical signs, while five displayed an attenuated phenotype. Findings among manifesting females included short stature, widow's peak, dysplastic ears, hypertelorism, anteverted nares, interdigital webbing, and brachydactyly.
5. Conclusion
This study expands the clinical and molecular spectrum of AAS by describing 14 patients with molecular confirmation. Our findings highlight the importance of considering AAS across the lifespan, with “low sperm count” serving as a diagnostic clue in adults and prenatally detected rhizomelia warranting inclusion in the differential diagnosis in fetal life.
The deep phenotyping approach allowed us to describe novel findings in multiple patients, including skin abnormalities, renal malformations, and muscular build, while providing evidence of second patients with osteochondritis dissecans and oligo/azoospermia, strengthening the association of these findings with AAS. It also revealed that cardiac and ocular involvement are more prevalent than previously reported.
Author Contributions
G.T.T., U.A., T.K., Ş.A., A.D.A., and H.K. contributed to the clinical evaluation of the patients. V.K. and Z.O.U. performed molecular analysis. H.K. designed and participated in the project supervision. G.T.T. wrote the manuscript which was reviewed by all co‐authors.
Ethics Statement
Ethical approval was provided by the local ethics boards of Istanbul University (2008/1194 for CRANIRARE and 2012/743‐1061 for CRANIRARE‐II) and Koç University (2015.120.IRB2.047 for CRANIRARE‐II).
Conflicts of Interest
The authors declare no conflicts of interest.
Peer Review
The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/cge.14744.
Supporting information
Data S1. Supporting Information.
Acknowledgments
We are grateful to the families for participating in this study. This work was partially presented at the European Human Genetics (ESHG) Conference in 2013 (P02.009) and 2024 (EP13.093). We cordially thank Hilal Pırıl Saraçoğlu, PhD student for her contribution on the graphical abstract which was partially created with BioRender.com.
Turgut G. T., Altunoglu U., Avcı Ş., et al., “Aarskog Syndrome: Deep Phenotyping and Genomic Landscape of a New Cohort Including Adult Patients,” Clinical Genetics 108, no. 3 (2025): 334–346, 10.1111/cge.14744.
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon request.