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Aarskog-Scott syndrome
This syndrome is characterised by short stature, unique facial characteristics, skeletal issues, and genital differences. It mainly affects males and is caused by changes in the FGD1 gene, influencing cell function and development.
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Overview
Aarskog-Scott syndrome is a rare inherited condition that affects various aspects of development, particularly growth, facial features, and the skeleton [PMID:20301473]. Individuals with this syndrome often have short stature and distinctive facial characteristics, such as a rounded face, widely spaced eyes (hypertelorism), a broad forehead, and a small nose. Skeletal differences, especially in the hands and feet, are also common. While it can affect females, symptoms are generally much milder in females than in males.
This syndrome is also known as facio-digito-genital dysplasia, which highlights the main areas of the body it affects: the face, fingers and toes (digits), and genitalia. The condition is present from birth, and its signs and symptoms can vary in severity among affected individuals.
Symptoms & clinical features
The symptoms of Aarskog-Scott syndrome are diverse, but certain features are frequently observed. Characteristic facial features include a rounded face, a broad forehead, a small nose with nostrils that point forward (anteverted nostrils), a 'shawl' scrotum where the skin surrounding the penis extends around the testicles, and a short groove between the nose and the upper lip (philtrum) [PMID:20301473].
Skeletal abnormalities typically involve the hands and feet, such as short fingers and toes (brachydactyly), curved fifth fingers (clinodactyly), and webbing between digits (syndactyly). Other skeletal signs can include a flattened back of the skull, broad thumbs and big toes, and joint laxity. In terms of growth, short stature is a common finding. Some individuals may also experience intellectual development differences, though this is not always present [PMID:20301473].
Genital anomalies are often observed in males, including the distinctive 'shawl' scrotum, undescended testes (cryptorchidism), and hypospadias, where the opening of the urethra is not at the tip of the penis. Dental issues, such as delayed tooth eruption or missing teeth, can also occur.
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Affected organs
Aarskog-Scott syndrome primarily impacts the skeletal system, leading to characteristic differences in the hands, feet, and overall stature. The face is also significantly affected, presenting with a particular set of features. Genital development, specifically in males, frequently shows anomalies.
Other body systems that may be affected include the brain, which can lead to intellectual developmental differences in some individuals. Dental structures can also be involved, with implications for oral health.
Risks & severity
The severity of Aarskog-Scott syndrome can vary considerably, even within the same family. Males typically experience more pronounced symptoms compared to females, who may have very mild or no noticeable signs. The condition is present from birth, and its features can become more apparent as a child grows.
While largely affecting physical development, some individuals, predominantly males, may experience mild to moderate intellectual developmental differences. Lifetime risks are generally related to the specific complications arising from skeletal or genital anomalies, such as fertility issues in affected males or orthopaedic concerns related to limb differences. The exact prevalence of Aarskog-Scott syndrome is not well established, but it is considered a rare condition.
Genetic causes
Aarskog-Scott syndrome is caused by pathogenic variants in the *FGD1* gene [PMID:20301473]. The *FGD1* gene provides instructions for making a protein involved in regulating cell growth and movement. Specifically, it acts as a guanine nucleotide exchange factor (GEF) for a protein called Cdc42.
Cdc42 is a small protein that plays a crucial role in forming the cell's internal framework (cytoskeleton) and influencing how cells interact and move. When the *FGD1* gene has a pathogenic variant, the FGD1 protein may not function correctly, or it may not be produced at all. This disruption can interfere with the normal activity of Cdc42, potentially leading to the developmental differences seen in Aarskog-Scott syndrome.
- FGD1 FYVE, RhoGEF and PH domain containing 1The FGD1 gene provides instructions for a protein that acts as a guanine nucleotide exchange factor, playing a key role in cellular signalling pathways critical for development, particularly bone formation.
Inheritance pattern
Aarskog-Scott syndrome has an X-linked recessive (XLR) inheritance pattern. This means the *FGD1* gene is located on the X chromosome, one of the two sex chromosomes. Females have two X chromosomes, while males have one X and one Y chromosome.
In XLR inheritance, males are typically more severely affected because they only have one X chromosome. If a male inherits an X chromosome with a pathogenic *FGD1* variant, he will develop the condition. Females, having two X chromosomes, usually need a pathogenic variant on both X chromosomes to be severely affected, which is very rare. Instead, females who carry one pathogenic variant often show no symptoms or only very mild ones. A carrier female has a 50% chance of passing the pathogenic variant to each child. A male with the condition will pass the X chromosome with the pathogenic variant to all his daughters, making them carriers, but will not pass it to his sons.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
Diagnosing Aarskog-Scott syndrome typically involves a clinical evaluation based on the characteristic physical features. However, a definitive diagnosis is confirmed through genetic testing to identify a pathogenic variant in the *FGD1* gene [PMID:20301473]. Genetic testing usually involves analysing a blood sample to sequence the *FGD1* gene.
In the UK, genetic testing for Aarskog-Scott syndrome falls under the NHS Genomic Medicine Service. Patients are usually referred for genetic testing by a paediatrician or a clinical geneticist. These specialists can assess a child's symptoms and growth patterns to determine if genetic testing is appropriate. The relevant R-codes for testing can be identified via the NHS National Genomic Test Directory. Genetic counselling is also an important part of the diagnostic process, providing information and support to families.
Management & lifestyle
Management of Aarskog-Scott syndrome focuses on addressing individual symptoms and developmental needs. This often involves a multidisciplinary team approach including paediatricians, clinical geneticists, orthopaedic specialists, and potentially developmental specialists or speech and language therapists. Regular monitoring of growth and development is key.
For skeletal issues, orthopaedic intervention may be considered if required. Genital abnormalities in males, such as undescended testes, might require surgical correction. Developmental support programs can help children reach their full potential. Genetic counselling is crucial to help families understand the inheritance pattern and potential implications for future family planning. There is currently no specific cure for Aarskog-Scott syndrome, so care aims to manage symptoms and improve quality of life.
UK care pathway
In the UK, individuals suspected of having Aarskog-Scott syndrome would typically enter the NHS Genomic Medicine Service pathway. Initial assessment often occurs through a paediatrician, who may then refer to a clinical genetics service. Clinical geneticists and genetic counsellors at these centres provide expert evaluation, coordinate genetic testing (guided by relevant PanelApp R-codes in the NHS National Genomic Test Directory), and offer support and information to families. This ensures a comprehensive approach to diagnosis and ongoing care within the NHS.
Frequently asked questions
Is Aarskog-Scott syndrome more common in males or females?
Aarskog-Scott syndrome is significantly more common and typically more severe in males due to its X-linked inheritance pattern. Females can be carriers and may show milder or no symptoms.
Can Aarskog-Scott syndrome affect intelligence?
While intellect can be typical, some individuals with Aarskog-Scott syndrome, predominantly males, may experience mild to moderate intellectual developmental differences. This varies among affected individuals.
How is Aarskog-Scott syndrome inherited?
The syndrome follows an X-linked recessive inheritance pattern. This means the gene responsible (*FGD1*) is on the X chromosome. Males are usually affected if they inherit a pathogenic variant, while females are often carriers with mild or no symptoms.
What kind of medical specialists would typically be involved in caring for someone with Aarskog-Scott syndrome?
Care for Aarskog-Scott syndrome usually involves a team including paediatricians, clinical geneticists, orthopaedic specialists for bone issues, and potentially developmental specialists or speech and language therapists.
Is there a cure for Aarskog-Scott syndrome?
Currently, there is no specific cure for Aarskog-Scott syndrome. Management focuses on addressing the individual symptoms and developmental needs through various medical and therapeutic interventions.
References
- Jeanne M, Ronce N, Remizé S. Aarskog-Scott syndrome: a clinical study based on a large series of 111 male patients with a pathogenic variant in FGD1 and management recommendations. Journal of medical genetics. 2025. PMID: 39798962
- Depeyre A, Schlund M, Gryseleyn R. Dental and Maxillofacial Signs in Aarskog Syndrome: A Review of 3 Siblings and the Literature. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2018. PMID: 29689188
- Adam MP, Bick S, Mirzaa GM. FGD1-Related Faciogenital Dysplasia (Aarskog-Scott Syndrome). 1993. PMID: 41704117
- Li S, Tian A, Wen Y. FGD1-related Aarskog-Scott syndrome: Identification of four novel variations and a literature review of clinical and molecular aspects. European journal of pediatrics. 2024. PMID: 38411716
- Zhu Y, Chen Q, Lin H. FGD1 Variant Associated With Aarskog-Scott Syndrome. Frontiers in pediatrics. 2022. PMID: 35911831
- Ahmed A, Mufeed A, Ramachamparambathu AK. Identifying Aarskog Syndrome. Journal of clinical and diagnostic research : JCDR. 2016. PMID: 28209013
- Grossen A, Gavula T, Chrusciel D. Multidisciplinary neurocutaneous syndrome clinics: a systematic review and institutional experience. Neurosurgical focus. 2022. PMID: 35535824
- Nayak RB, Ambika L, Bhogale GS. Mania with Aarskog-Scott syndrome. Indian pediatrics. 2012. PMID: 22565081