Aarskog-Scott syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Synonyms and Keywords: Aarskog disease, Aarskog-Scott syndrome, AAS, Faciodigitogenital syndrome, Faciogenital dysplasia, FGDY, Scott Aarskog syndrome

Overview

Aarskog-Scott syndrome is a rare inherited disease distinguish by short stature, facial abnormalities, skeletal and genital anomalies. The Aarskog-Scott syndrome (AAS) is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and facial genital dysplasia. In The United States of America in order to categorise a condition as a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed on 1983 by congress for the rare diseases. Today an average of 25-30 million americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number.

Historical Perspective

• In 1970, Aarskog-Scott syndrome (AAS) was first described by Aarskog, a Norwegian pediatrician and human geneticist.
• In 1971, Scott described the association between ligamentous laxity which results in hyperextensibility of the fingers, genu recurvatum, flat feet and Aarskog-Scott syndrome (AAS).
• In 1973, Sugarman et al described an Mexican-American family in which 2 half brothers and their 2 maternal uncles had Aarskog syndrome.
• In 1993, Teebi et al suggested that the disease Aarskog-Scott syndrome (AAS) follows autosomal dominant inheritance.
• In 1978, Escobar and Weaver described a patient who is had symptoms of Noonan syndrome than Aarskog-Scott syndrome (AAS).
• In 1981, Grier et al. suggested that Aarskog-Scott syndrome (AAS) follows autosomal dominant pattern of inheritance.
• In 1984, Van den Bergh et al. mentioned a patient with Aarskog-Scott syndrome (AAS) development of syndrome of benign intracranial hypertension after minor head trauma.
• In 1994, Fernandez et al. mentioned 10 Japanese patients who are positive with Aarskog syndrome.
• In 1998, Logie and Porteous concluded that in patients with Aarskog-Scott syndrome (AAS) have normal intelligence.
• In 2002, Lebel et al. is the one who found a missense mutation in the FGD1 gene.
• In 2005, Orrico et al. described attention deficit-hyperactivity disorder (ADHD) in patient with Aarskog-Scott syndrome (AAS).
• In 2010, Orrico et al. genetically confirmed 11 patients for Aarskog-Scott syndrome.

Detection of FGD1 mutations. (A) Schematic representation of the domains of the FGD1 protein showing mutations (p.Glu380* and p.Gln664*) identified in patients with AAS. Arrows indicate the positions of the mutated nucleotides in FGD1. (B) sequencing results (p.Glu380* and p.Gln664*) detected in exon 5 and 12, respectively. The altered amino acids are shown in red. Case courtesy by Mariana Pérez-Coria et al

Classification

• There is no established system for the classification of Aarskog-Scott syndrome (AAS).

Pathophysiology

• Aarskog-Scott syndrome (AAS) is transmitted in X-linked recessive mode of inheritance.
• In some cases Aarskog-Scott syndrome (AAS) is transmitted in autosomal dominant mode of inheritance.
• It is understood that Aarskog-Scott syndrome (AAS) is the result caused by a mutation in FGD1 gene.
• FGD1 gene mapped to the Xp11.21 region is located on X chromosome.
• Normally, in most of the situations males have one X chromosome and females have two X chromosomes.
• When mutation occurs in FGD1 gene of males may result in the Aarskog-Scott syndrome (AAS).
• But, in females the mutation had to occur in both X chromosomes to manifest the disease Aarskog-Scott syndrome (AAS).
• In females if the mutation occurs in only one X chromosome then it results in mild features of Aarskog-Scott syndrome (AAS).
• The gene FGD1 specifically encodes for guanine nucleotide exchange factor (GEF).
• Guanine nucleotide exchange factor (GEF) inturn activates Cdc42 which belongs to Ras homology of the p21 GTPases.
• Upon activation of Cdc42, FGD1 proteins they activate the following:
  • Fibroblasts
  • Cytoskeletal elements which are involved in
    • Cellular signaling
    • Adhesion
    • Migration
  • c- N-terminal kinase (JNK) signaling cascade which involves:
    • Cell growth
    • Apoptosis
    • Cellular differentiation
• These abnormalities of FGD1/Cdc42 signaling pathway may produce an defective embryonic development and abnormal endochondral and intramembranous bone formation and leads to Aarskog-Scott syndrome (AAS).

Causes

Genetic Cause

• Aarskog-Scott syndrome (AAS) is caused by a mutation in the FGD1 gene.

Differentiating Aarskog-Scott syndrome from other Diseases

• Aarskog-Scott syndrome (AAS) must be differentiated from Robinow syndrome, Noonan syndrome, pseudohypoparathyroidism, Silver-Russell and SHORT syndrome.

Epidemiology and Demographics

Incidence

• The incidence of Aarskog-Scott syndrome (AAS) is unknown.
• Till now there are 29 cases of Aarskog-Scott syndrome (AAS) had been diagnosed worldwide.

Prevalence

• The prevalence of Aarskog-Scott syndrome (AAS) is 1/25 000 worldwide.
• The prevalence of Aarskog-Scott syndrome (AAS) is 1-9 per 1,000,000 in Europe.

Age

• Aarskog-Scott syndrome (AAS) commonly affects individuals of younger age especially in childwood.

Race

• There is no racial predilection to Aarskog-Scott syndrome (AAS).

Gender

• Aarskog-Scott syndrome (AAS) affects men more commonly than in women.

Risk Factors

There are no established risk factors for Aarskog-Scott syndrome (AAS).

Screening

There is insufficient evidence to recommend routine screening for Aarskog-Scott syndrome (AAS).

Natural History, Complications and Prognosis

Natural History

• The symptoms of Aarskog-Scott syndrome (AAS) usually develop in the first decade of life, and start with symptoms such as delayed growth spurt.
• The symptoms of Aarskog-Scott syndrome (AAS) typically develop in 2 to 4 years of age.

Complications

• Common complications of Aarskog-Scott syndrome (AAS) include:
  • Cryptorchidism
  • Spina bifida occulta
  • Cervical spine abnormalities
  • Scoliosis
  • Camptodactyly
  • Lymphoedema
  • Optic nerve hypoplasia
  • Retinal vessel tortuosity

Prognosis

• Prognosis is generally good with Aarskog-Scott syndrome (AAS) patients.

Diagnostic study of choice

• Aarskog-Scott syndrome (AAS) is primarily diagnosed based on clinical presentation based on Teebi criteria which includes:
  • Short stature
  • Hypertelorism
  • Fold of the lower lip
  • Brachydactyly
  • Interdigital webbing
  • Shawl scrotum
  • Long philtrum
  • Mild facial hypoplasia

Patients with clinical features of Aarskog syndrome-(A) Patient 1; note distinctive facial characteristics and interdigital tracts in both hands. (B) Patient 2; discrete facial features and the shawl scrotum can be appreciated. (C) Patient 3 and his mother (patient 8); note prominent forehead, widow's peak, hypertelorism, and fold under the lower lip. (D) Patient 4 with widow's peak, midface hypoplasia, ptosis, clinodactyly, and brachydactyly. (E) Patient 5, brother of patient 4, with distinctive facial features, clinodactyly, and brachydactyly. Case courtesy by Mariana Pérez-Coria et al

History and Symptoms

Common Symptoms

Common symptoms of Aarskog-Scott syndrome (AAS) include:

• Short stature (evident by 1-3 years of age)
• Mental retardation
• Hypertelorism
• Umbilical hernia
• Shawl scrotum
• Hypospadias
• Undescended testes

Physical Examination

HEENT

Facial features are very prominent and important for the diagnosis of Aarskog-Scott syndrome (AAS) which include:

• Round face
• Facial edema with downward slanting palpebral fissures
• Short nose along with anteverted nares
• Long philtrum
• Ocular hypertelorism with ptosis
• Maxillary hypoplasia
• A broad upper lip with a crease below the lower lip
• Abnormal auriculares

Neck

• Short neck
• Webbing of sides of the neck

Chest

• Mild pectus excavatum (sunken chest)

Abdomen

• Protruding navel
• Inguinal hernias

Genitourinary

• Shawl Scrotum
• Undescended testicles

Extremities

• Small, broad hands and feet
• Short fingers and toes (brachydactyly)
• Clinodactyly
• Mild webbing between the fingers and toes
• Simian crease
• Broad thumbs and big toes

Laboratory Findings

• There are no diagnostic laboratory findings associated with Aarskog-Scott syndrome (AAS).

Electrocardiogram

• There are no ECG findings associated with Aarskog-Scott syndrome (AAS).

X-Ray Findings

• 

  Scoliosis- a) Early postoperative X-ray (b) 10 years follow-up X-ray.Case courtesy Kerim Sariyilmaz

  There are no x-ray findings associated with Aarskog-Scott syndrome (AAS). However, an x-ray may be helpful in the diagnosis of complications of Aarskog-Scott syndrome (AAS), which include:
  • Skeletal abnormalities
  • Tooth abnormalities
  • Scoliosis

Echocardiography and Ultrasound

• The ultrasound can help in detecting the undescended testis associated with Aarskog-Scott syndrome (AAS).

CT-Scan Findings

• Head CT scan may be helpful in the diagnosis of Aarskog-Scott syndrome (AAS). Findings on CT scan suggestive Aarskog-Scott syndrome (AAS) include:
  • Cystic development

MRI Findings

• There are no MRI findings associated with Aarskog-Scott syndrome (AAS).

Medical Therapy

• There is no treatment for Aarskog-Scott syndrome (AAS); the mainstay of therapy is symptomatic care.
• Patients with short stature are treated with growth hormone, which shows promising results in increasing the height of the patients.

Interventions

• There are some recommended therapeutic interventions for the management of Aarskog-Scott syndrome (AAS), which includes speech pathologists, audiologists and eye specialists who can improve the quality of the patient's life.

Surgery

• Surgery is usually reserved for patients with congenital or structural malformations which involves the following:
  • Hypospadias(opening of the penis is on the underside rather than the tip)
  • Inguinal or umbilical hernias
  • Cryptorchidism(undescended testis)

Primary Prevention

• There are no established measures for the primary prevention of Aarskog-Scott syndrome (AAS).

Secondary Prevention

• There are no established measures for the secondary prevention of Aarskog-Scott syndrome (AAS).