Aarskog syndrome, a genetic developmental disorder, affects many body systems across an individual. Given the low prevalence of the disease, awareness and understanding of these clinical features and symptoms are essential for both patients and healthcare professionals, to ensure a timely and accurate diagnosis of Aarskog syndrome. This ensures patients receive the correct diagnosis which will allow access to the most effective treatment for their disease.
In this article, we will explore all symptoms that have been documented in Aarskog syndrome. This ranges from the most common facial and genital clinical features to other rare symptoms associated with the disease. Management and treatment strategies for the main Aarskog syndrome symptoms will also be discussed.
Introduction
Aarskog syndrome is a very rare developmental disorder which affects an individual’s height, facial, muscles, skeleton, and genital features. It is also known as Aarskog-Scott Syndrome and is a genetic disease which can be inherited within families. First discovered in 1970, it has a low prevalence among the general population, with less than 100 individuals with Aarskog syndrome clinically reported. However, it is believed that 1 in 25,000 people may have Aarskog syndrome and its low prevalence is due to low diagnosis rates and less awareness of this rare disease.
Causes of aarskog syndrome
Aarskog syndrome is a genetic disease associated with the FGD1 gene found on the X chromosome. When errors are made in the FGD1 gene, it can result in the manifestation of the disease.1,2 While people assigned female at birth (AFAB) possess two copies of the X chromosome, people assigned male at birth (AMAB) only possess one X chromosome copy. Therefore, the disease predominately affects people with AMAB, although people with AFAB can also exhibit Aarskog syndrome symptoms, albeit with milder severity.
However, likely, errors in other genes can also cause Aarskog syndrome. Currently, only about 20% of people AMAB with the disease have a detected FDG1 gene error. Given that the clinical features and symptoms of Aarskog Syndrome also greatly vary between individuals, other genes are likely implicated in the disease.
Clinical features and symptoms
Aarskog syndrome is characterised by various facial, skeletal, genital, and developmental abnormalities. We explore these below, with brief descriptions provided for each of the clinical features and symptoms of Aarskog syndrome.3,4
Facial symptoms
- Widow's peak hairline: A distinct point in the middle of the hairline
- Widely spaced eyes
- Downward palpebral slant: This describes the downward slanting of the outer corners of the eyes
- Ptosis: Droopy eyelids
- Broad nasal bridge
- Anteverted nostrils: Nostrils that tilt forward
- Small nose and rounded face
- Maxillary hypoplasia: This describes the poor development of the middle section of the face, normally in the upper jawbone area
- Transverse crease below the lower lip
- Long philtrum: A groove present above the upper lip
- Distinct ear shape: Individuals with Aarskog syndrome have ears that are positioned lower on the head and stick out more than usual, with fleshy earlobes
Skeletal symptoms
- Short stature
- Broad, short hands and feet: This also includes brachydactyly, which describes short, stubby fingers
- Clinodactyly: The presence of a curved-in fifth finger
- Proximal interphalangeal joint hypertension: The ability to bend the middle joints of fingers backwards to an abnormal extent
- Distal interphalangeal joint flexion: This describes joints bending near the fingertips
- Webbing of fingers and toes (normally mild)
- Wide, flat feet with round bulbous toes
- Pectus excavatum: Individuals with Aarskog syndrome can have a chest that is sunken/caved-in
- Spinal abnormalities: This commonly includes the incomplete closure of the spinal bones (spina bifida occulta) or fusion of neck vertebrae
- Inguinal hernia: The protrusion of abdominal contents in the groin area
- Umbilicus: A belly button that sticks out more than usual
Webbed hands or feet are one of the skeletal/physical symptoms of Aarskog syndrome (Photo credits: commons.wikimedia.org)
Genital symptoms
- Shawl scrotum: This refers to an abnormal fold of skin at the base of the penis
- Cryptorchidism: Undescended testicles
- Macroorchidism: Large testicles
- Hypospadias: This describes when the urinary opening is found on the underside of the penis
- Bifid scrotum: A scrotum that appears split or divided
- Delayed sexual maturity: Individuals with Aarskog syndrome commonly undergo delayed development of sexual characteristics
Developmental and neurodevelopmental symptoms
- Mild to moderate learning difficulties
- Learning and behavioural disabilities: These are present mostly in early childhood
- Delayed teeth eruption
- Enamel hypoplasia: Thin or missing enamel, the hard outer layer of teeth
- ADHD symptoms5: This includes hyperactivity, attention deficit, and impulsivity
- Slow growth and weight gain
- Frequent (and often chronic) respiratory infections
Rare symptoms documented in few aarskog syndrome
- Congenital heart defects
- Scoliosis: The abnormal curvature of the spine
- Extra pairs of ribs
- Cleft palate or cleft lip: The presence of an opening in the roof of the mouth or a split in the upper lip
- Eye and vision abnormalities
- Overweight
Diagnosis of aarskog syndrome
Diagnosis of Aarskog syndrome is achieved firstly by recognition of the main physical symptoms, such as short stature, facial features, and genital abnormalities. Subsequently, a molecular genetic test will be performed to characterise a potential FGD1 gene error which can confirm the diagnosis.
If no FGD1 gene error is detected, the individual may still be diagnosed with Aarskog syndrome as most cases do not have a detected causative gene error. However, other diseases with similar clinical features and symptoms should also be thoroughly evaluated by the healthcare professional. Diseases with similar presentation to Aarskog syndrome include:
- Noonan syndrome
- SHORT syndrome
- Robinow syndrome
- Pseudohypoparathyroidism
Management and treatment of aarskog syndrome
There is currently no curative treatment for Aarskog syndrome. However, symptoms of the disease are often treated and managed individually. Given the great range of symptoms that may appear in an individual with Aarskog syndrome, these treatments are often prescribed for each unique case and can involve a great team of healthcare professionals which include paediatricians, dentists, audiologists, and ophthalmologists.
An initial health assessment should be conducted to thoroughly understand an individual’s symptoms of Aarskog syndrome. This can include:
- X-rays: To identify any structural and skeletal abnormalities
- Hearing and vision tests: To check whether the Aarskog syndrome patient has any ear or eye problems
- Dental tests: To identify issues with regular dental development which is a common symptom of individuals with Aarskog syndrome
- Neurodevelopmental evaluation
These assessments are regularly repeated over the individual’s lifetime to ensure that all clinical features of Aarskog syndrome are accounted for in the patient’s care.
Growth hormone treatment has been administered to children with Aarskog syndrome to treat their developmental delay.6 However, initial results do not indicate a significant improvement in these treatments.
Conclusions
In conclusion, Aarskog syndrome is a rare genetic disease which causes a large range of clinical features and symptoms in individuals. These symptoms range across skeletal, facial, genital, developmental, and neurodevelopmental features. Abnormalities in facial, genital and skeletal features are the characteristic hallmark of Aarskog syndrome. Treatment for Aarskog syndrome focuses on treating and managing each of these individual symptoms to support each case uniquely.
References
- Schwartz CE, Gillessen-Kaesbach G, May M, Cappa M, Gorski J, Steindl K, et al. Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome. Eur J Hum Genet. 2000 Nov;8(11):869–74.
- Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, Hertz JM, et al. Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene. Am J Med Genet A. 2010 Feb;152A(2):313–8.
- Shalev SA, Chervinski E, Weiner E, Mazor G, Friez MJ, Schwartz CE. Clinical variation of Aarskog syndrome in a large family with 2189delA in the FGD1 gene. Am J Med Genet A. 2006 Jan 15;140(2):162–5.
- Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns JP, Crushell E, et al. Phenotypic and molecular characterisation of the Aarskog–Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. Eur J Hum Genet [Internet]. 2004 Jan [cited 2024 Jun 29];12(1):16–23. Available from: https://www.nature.com/articles/5201081
- Orrico A, Galli L, Buoni S, Hayek G, Luchetti A, Lorenzini S, et al. Attention-deficit/hyperactivity disorder (Adhd) and variable clinical expression of Aarskog-Scott syndrome due to a novel FGD1 gene mutation (R408q). Am J Med Genet A. 2005 May 15;135(1):99–102.
- Satoh M, Yokoya S. Anabolic steroid and gonadotropin releasing hormone analog combined treatment increased pubertal height gain and adult height in two children who entered puberty with short stature. J Pediatr Endocrinol Metab. 2006 Sep;19(9):1125–31.
