Introduction

Aarskog Syndrome also known as Aarskog-Scott syndrome (ASS) or Faciogenital Dysplasia (FGDY) is a rare maternal inherited disease caused by a mutation in the FGD1 gene. The prevalence of the aarskog syndrome is about 1/25000. The mutation occurs in the short X chromosome which encodes a guanine nucleotide exchange factor (GEF). This factor is responsible for the activation of a protein-coding gene named CDC42. It participates in the organisation of division and movement of cell growth regulation and normal embryonic development.^1,2,3

Clinical diagnosis of aarskog syndrome

AAS has several heterogeneous features classified into primary, secondary, and other.²

Primary criteria

Craniofacial characteristics

Craniofacial characteristics were found to be the most common. It can include several different characteristics such as: 

• Hypertelorism (Eyes are abnormally distant)
• The nose could be short or the nostrils are flared forward (anteverted nares)
• Folded bottom lip

Orthopaedic features

Orthopaedic features can be seen in around 18.1% of patients and they can include:²

• Short stature
• Brachydactyly/ wide fingers
• Clinodactyly: impairment of the radial angulation at an interphalangeal joint in the radio-ulnar or palmar planes. It mostly affects the fifth finger

Neurological and ophthalmological manifestations

Neurological and ophthalmological characteristics can be seen in 25.8% of patients and include the following features:²

• Developmental delay
• Attention deficit hyperactivity disorder (ADHD)

The following can also be found however less common: 

• Sleep disorder
• Omphalocele

Ophthalmological impairments are less frequent and can be: 

• Strabismus (Most frequent) 
• Myopia
• Amblyopia

Genitourinary tract impairments

These impairments were found in 8.6% of people and include features such as: 

• Shawl scrotum
• Cryptorchidism
• Hypospadias
• Micropenis
• Vesicoureteral reflux
• Hydrocele

Secondary and additional features

Craniofacial traits

• Ptosis (drooping of the upper eyelid over the eye)
• Widow’s peak
• Dysplastic ears
• Long philtrum
• Frontal bossing
• Midface hypoplasia
• Dental malocclusions
• Retrognathia
• Preauricular tag
• Epicanthal fold (Monolid eyes)

Orthopaedics features

• Metatarsus varus: deformity of the foot where the forefoot turns inward
• Coxa magna: deformation of the head and the neck of the femur (the sole bone of the thigh)
• Arthrogryposis (stiffness of multiple joints)²

What happens in females with aarskog syndrome?

The carriers are asymptomatic or have a milder form of the syndrome. They have the following features:

• Brachydactyly (short fingers)
• Hypertelorism
• Widow’s peak

Differential diagnosis

Noonan syndrome

It is a rare autosomal dominant disease with a prevalence of 1/2000-2500. Unlike AAS, it can be seen in both males assigned at birth and females assigned at birth. Noonan syndrome is inherited by one of the parents in 50% of the cases. On the other hand, some cases are sporadic meaning it is not necessarily inherited (i.e. de novo) and the altered genes play a role in the RAS/MAPK cell signaling pathway.^5,6

Signs of noonan syndrome

• Craniofacial features e.g. set eyes and low-set ears
• Ophthalmological and nervous symptoms e.g strabismus, hearing loss, developmental delay, and learning
• Orthopaedics and skeletal features such as short stature, pectus carinatum, pectus excavatum, and scoliosis
• Urogenital features including cryptorchidism (can lead to infertility in males)
• In utero diagnosis
• Heart problems: pulmonary valve stenosis and hypertrophic cardiomyopathy
• Predisposition to tumours
• Lymphatic dysplasia (with a possible lymphoedema in extremities and abdomen)
• Coagulopathy⁶

Treatment and prognosis

The prognosis depends on the severity. However, it needs lifelong management due to the possible fatal impairments it can cause with key organs such as the heart and the increased predisposition to tumours. There is no known treatment however, potential treatments include:

• Growth hormones (HGH)
• Specific drugs (RAS/MAPK modulators)

Robinow syndrome 

It is a sporadic autosomal dominant syndrome. Around 80 families have been found with  Robinow Syndrome. Various genes are linked to Robinow syndrome including DVL1, DVL3, or WNT5A.⁷ 

Clinical features

• Orthopaedic features: short stature and brachydactyly
• Genital abnormalities: micropenis / webbed penis and cryptorchidism
• Craniofacial features: hypertelorism frontal bossing, anteverted nares, and midface retrusion
• Cognitive delay (rare)
• Vertebral abnormalities: hemivertebrae, scoliosis, and nail dysplasia
• Genital abnormalities: in males hypoplastic scrotum and females hypoplastic clitoris and labia majora
• Craniofacial impairments: tongue bilobed, macrocephaly, and cleft lip/palate
• Dental features: malocclusion, crowding, hypodontia, and late eruption of permanent teeth
• Renal abnormalities
• Cardiac features: abnormalities in the development of the heart valves and some large vessels of the heart
• Abdominal issue: can cause an umbilical hernia
• Nervous system issues: hearing loss (bilateral)

Treatment and prognosis

Treatment of Robinow syndrome is based on the symptoms seen and will require a multidisciplinary approach to target the condition. The life expectancy depends on the presence of severe impairments such as heart defects.

Smith-lemli-opitz syndrome 

Smith-Lemli-Opitz Syndrome is a recessive autosomal inherited rare disease. The incidence levels are 1/10000 to 70,000 in newborns. There is a high perinatal mortality in severe cases and misdiagnosis in mild cases. A mutation in the gene coding for 7-dehydrocholesterol reductase (DHCR-7) is the main genetic cause of Smith-Lemli-Opitz syndrome. This leads to a defect in cholesterol synthesis. The impairment arises from the primary role of cholesterol in various processes throughout intrauterine development, such as:⁸

• Hormone production (specifically the progesterone hormone) 
• Development of structures such as neural tubes,  limbs the  brain, and the heart

Clinical features

• Genital features e.g. hypospadias
• Orthopaedic and skeletal features e.g. delay in growth and syndactyly
• Facial dysmorphisms e.g. microcephaly, micrognathia, bilateral ptosis, bitemporal narrowing, cleft palate, and a short upturned nose
• Nervous signs e.g. a learning disability

Diagnosis

• Assessment of foetal anomalies
• Echography for morphologic abnormalities in organs
• In the blood a false positive of an increase in cholesterol levels

Treatment and prognosis

The treatment depends on the symptoms. Potential treatment options include:

• Contribution of dietary cholesterol and bile acid therapy: improvement in growth, the autism spectrum disorder, and sleep
• Supportive care for feeding: feeding via nasogastric or a gastrotomy
• Surgery if needed

The life expectancy is short in Smith-Lemli-Opitz Syndrome. During the early years, the mortality rate is above 20%. The main cause of death tends to be gastrointestinal issues such as:

• Malnutrition
• Sudden causes of infection
• Hypoglycemia
• Adrenal insufficiency
• Malignant hyperthermia: temperature can reach up to 40.6 °C 
• Gastrointestinal complications
• Aggressive behaviours
• Heart failure and chronic renal failure

Differences to aarskog syndrome

• Genital features: ambiguous genitalia, sex reversal, and  hypospadias in male
• Growth issues: restricted growth in utero,  abnormal fingerprints, postaxial  and 
• Central nervous system: hypotonia, absence or malformations of some parts of the brain
• Cardiovascular: ostium primum, atrial septal defects, patent ductus arteriosus and atrioventricular canal
• Renal and adrenal features: malformations of kidneys and adrenal glands
• Underdeveloped external genitalia
• Respiratory problems: abnormalities of the tracheal and laryngeal cartilage
• Gastroenterology: gastroesophageal reflux disease (GERD), pyloric stenosis,  Hirschsprung disease, intestinal dysmotility, and cholestatic liver disease

Turner syndrome 

Turner syndrome is a genetic disorder in females resulting from the absence or abnormalities on the X chromosome. However, it is not an inherited disorder. The prevalence is 1 in 2000 to 1 in 2500 live female births. It is not caused by a mutation of a gene. The impairment of X chromosomes occurs during division (meiosis) in germinal cells.⁹

How to distinguish turner syndrome

Similarities to aarskog syndrome

• Short stature
• Cardiovascular manifestations
• Intelligence is normal in Turner syndrome. Nevertheless, some learning disabilities may be seen such as calculations, memory, and  attention difficulties)
• Ophthalmologic abnormalities  e.g. hypertelorism, red-green color blindness, myopia or hypermetropia,  strabismus; amblyopia and ptosis

Differences to aarskog syndrome

• Chromosome number: in Turner Syndrome, there are 45 X chromosomes whilst in AAS there are 46 XX chromosomes in females
• Hormonal trouble: leads to impairment of the sexual hormone and the anti-mullerian hormone (AMH)
• Genital impairments: streak gonads which consist of the absence or rare undeveloped follicles leading to infertility
• Auto-immune disorders: coeliac disease and inflammatory bowel disease
• Tumour: gonadoblastoma a benign tumor of the ovaries
• Cardiovascular impairments: cardiac and aorta abnormalities (electrocardiogram (EKG) abnormalities)
• Renal manifestations: malformations of the kidneys or ureteropelvic junction abnormalities

Treatment and prognosis

The mortality rate is three times higher than the general population and treatment is dependent on the symptoms including:

• Growth Hormone therapy
• Cardiovascular medication
• Antihypertensive drugs
• Ovarian failure: Oestrogen replacement therapy
• Osteoporosis treatment
• Other deficiencies: Supplementation of vitamin D, Monitoring of the lipid blood and hyperglycemia, Monitoring of the liver function
• Measurement of the thyroid hormone (TSH)

Summary

Aarskog Syndrome, also called Aarskog-Scott syndrome or Faciogenital Dysplasia, is a rare inherited condition linked to mutations in the FGD1 gene on the X chromosome. It affects cell growth and development in mammals, with a prevalence of about 1 in 25,000. Diagnosis focuses on various clinical features divided into primary, secondary, and additional characteristics, including craniofacial traits, orthopaedic issues, and neurological symptoms. Differential diagnoses include Noonan syndrome, Robinow syndrome, Smith-Lemli-Opitz syndrome, and Turner syndrome. Treatment varies based on the specific symptoms and may include supportive care and hormone therapies. The prognosis depends on the severity of symptoms and can involve lifelong management for potential complications.