Aarskog-Scott syndrome Q87.1

The disorder was first described by Aarskog in 1970 and then described in detail by Scott in two different families with several affected males.

Aarskog described short stature individuals with craniofacial anomalies such as hypertelorism, short nose, ptosis and genital dysmorphism such as shell scrotum and cryptorchidism in association. Scott, on the other hand, described the same features in three different patients in 1971. In addition, various degrees of neurocognitive and/or behavioral disabilities were reported, ranging from attention deficit hyperactivity disorder (ADHD) to severe mental retardation. In most cases, however, the individuals affected by AAS had an average IQ

Aarskog-Scott syndrome, also known as facio-genital dysplasia, is a rare X-linked syndrome with recessive inheritance (OMIM:300546).

The syndrome is caused by mutations in the FGD1 gene. This gene is mapped on the short arm of the X chromosome (Xq11.22) and codes for a guanine nucleotide exchange factor (GEF). The GEF then activates Cdc42, which is directly involved in cytoskeletal organization, growth regulation and normal embryonic development in all mammals.

To date, 52 different pathogenic variants have been detected in the FGD1 gene in AAS (Parıltay D et al. 2016). Although a correlation between the variants and the spectrum of clinical expression in AAS patients has been intensively studied, no clear phenotype-genotype correlation has been established. The syndrome is clinically and genetically heterogeneous; in addition to FGD1, other genes that have not yet been characterized may be involved in the pathogenesis. The low detection rate could be explained by cases that have been clinically diagnosed but for which no supporting molecular data are available.

The cause is a mutation in the SGD1 gene.

Clinical Presentation (symptoms cited from Li S et al. 2024)
Primary Criteria (incidence of the symptom in % shown in parentheses) 

• Hypertelorism (94.8)
• Short stature (82.8)
• Narrow scrotum (79.3)
• Anteverted nostrils/short nose (75.9)
• Brachydactyly/wide fingers (62.1)
• Clinodactyly (43.1)
• Short/wide hands (39.7)
• Interdigital web (34.5)
• Kamptodactyly (32.8)
• Syndactyly (24.1)
• Lower lip crease (5.2)

Secondary criteria

• Ptosis (58.6)
• Cryptorchidism (50.0)
• Joint hypermobility (50.0)
• Widow's Peak (46.6)
• Dysplastic ears (41.4)
• Downward-sloping eyelids (39.7)
• Inguinal hernia (36.2)
• Wide feet (31.0)
• Umbilical hernia (15.5)
• Protruding navel (6.9)

Additional criteria

• Long philtrum (55.2)
• Simulation lines (34.5)
• Frontal protrusion (27.6)
• Midface hypoplasia (20.7)
• Developmental delay (17.2)
• Delayed bone age (12.1)
• Obesity (10.3)
• Malocclusion (5.2)
• Hypospadias (1.7)

Other

• Fold under the lower lip (19.0)
• Low-set ears (19.0)
• Round face (17.2)
• Contracture of the interphalangeal joint (15.5)
• Receding gums (15.5)
• Pectus excavatum (13.8)
• Broad nasal bridge (12.1)
• Micrognathia (12.1)
• Short neck (12.1)
• ADHD (10.3)

1. Aarskog D (1970) A familial syndrome of short stature associated with facial dysplasia and genital anomalies. Journal of Pediatrics (St. Louis) 77: 856-861
2. Closs LQ et al (2012) Aarskog-scott syndrome: a review and case report. Int J Clin Pediatr Dent 5:209-212
3. Li S et al. (2024) FGD1-related Aarskog-Scott syndrome: Identification of four novel variations and a literature review of clinical and molecular aspects. Eur J Pediatr 183:2257-2272
4. Parıltay D et al. (2016) The human gene mutation database: towards A comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Human Genetics 136:665-677.
5. Pérez-Coria F et al. (2015) Identification of novel mutations in Mexican patients with aarskog-scott syndrome. Molecular Genetics & Genomic Medicine 3:197-202.
6. Ronce D et al. (2012) Unusual Facies, Joint Hypermobility, Genital Anomaly and Short Stature: A New Dysmorphic Syndrome. New York, NY, USA: National Foundation-March of Dimes