Ocular anomalies reported in FGFR2-related craniosynostosis include refractive errors, exophthalmos, and strabismus. Anterior segment anomalies have occasionally been reported in cases of FGFR2-related craniosynostosis. We report a three-year-old boy with unilateral Peters anomaly, short stature, facial dysmorphism, posterior plagiocephaly, heart defects, and developmental delay. His maternal half-sister had bilateral posterior embryotoxon, dysmorphism, brittle teeth, umbilical hernia, developmental delay, heart defects, and microcephaly. Their mother had a normal slit lamp exam. A novel variant was found in FGFR2 (NM_000141.4: c.1376T>G p.(Met459Arg)) in the proband and maternal half-sister. No other variants of interest were identified in anterior segment genes. Incidentally, we identified a hemizygous variant in FGD1 (NM_004463.3: c.1292dupT p.(His432Profs*8)) in the proband; heterozygous in the mother. FGD1 is associated with Aarskog-Scott syndrome (AAS) while FGFR2 is linked with 14 different phenotypes. The proband's features suggest AAS except for Peters anomaly and heart defects, which have been reported with FGFR2 variants. The shared novel FGFR2 variant suggests a dual diagnosis for the proband. Our findings support a role for FGFR2 in anterior segment development and broaden the genotypic and phenotypic spectrum of FGFR2-related disorders.

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.

Objectives/Background: Aarskog-Scott syndrome (AAS), also known as faciogenital dysplasia, is a rare X-linked genetic disorder primarily characterized by its diverse physical manifestations. Previous evidence suggests a potential association between AAS and neurodevelopmental disorders, including autism spectrum disorder (ASD). Methods: This case study presents a male adolescent with ASD and a novel genetic variant in FGD1 underlying AAS. We conducted comprehensive clinical, genetic, and behavioral assessments to characterize the neurodevelopmental presentation. Moreover, we examined the existing literature on AAS and comorbid neurodevelopmental disorders. Results: The patient demonstrated features consistent with both AAS and ASD, presenting with characteristic physical features of AAS and meeting diagnostic criteria for ASD on both ADI-R and ADOS-2. Cognitive assessment revealed above-average nonverbal IQ (Leiter-3, NVIQ = 115), while adaptive functioning was notably impaired (Vineland composite score = 65). Executive function deficits were identified through several assessments, though ADHD diagnostic criteria were not met. The literature review considered 64 studies, including 151 individuals with AAS. ASD was observed in 4.0%, Attention Deficit/Hyperactivity Disorder (ADHD) in 10.6%, and Intellectual Disability (ID) in 14.2% of cases. Conclusions: The combination of ASD with preserved nonverbal intelligence but impaired adaptive functioning in this AAS case demonstrates the complex neurodevelopmental manifestations possible in this rare genetic condition. The prevalence of neurodevelopmental disorders among people with AAS may be higher than their prevalence in the general population. However, a comprehensive assessment of developmental progress was rarely performed in previous studies, which may lead to systematic underestimation of co-occurring neurodevelopmental difficulties in AAS.

Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the FGD1 gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients. Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in FGD1, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders. This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations. A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of FGD1 variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients.

Patients with Aarskog-Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype-phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism.   Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: • Aarskog-Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: • We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype-phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function.