Aarskog-Scott syndrome
Encyclopedia
Aarskog–Scott syndrome is an inherited disease characterized 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 faciogenital dysplasia.
, downslanting palpebral fissure
s, anteverted nostrils, joint laxity, shawl scrotum, and mental retardation. The physical phenotype
varies with age and postpuberal males may have only minor remnant manifestations of the prepuberal phenotype.
Aarskog–Scott syndrome is transmitted in an X-linked recessive
manner. The sons of female carriers are at 50% risk of being affected with the syndrome. The daughters of female carriers are at 50% risk of being carriers themselves. Females may have mild manifestations of the syndrome. The syndrome is caused by mutation
in a gene
called FGDY1 in band p11.21 on the X chromosome
.
gene. FGD1 encodes a guanine nucleotide exchange factor
(GEF) that specifically activates Cdc42
, a member of the Rho (Ras homology) family of the p21 GTPase
s. By activating Cdc42, FGD1 protein
stimulates fibroblast
s to form filopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 protein also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis
, and cellular differentiation.
Within the developing mouse skeleton, FGD1 protein is expressed in precartilaginous mesenchymal condensations, the perichondrium
and periosteum, proliferating chondrocyte
s, and osteoblast
s. These results suggest that FGD1 signaling may play a role in the biology of several different skeletal cell types including mesenchymal prechondrocytes, chondrocytes, and osteoblasts. The characterization of the spatiotemporal pattern of FGD1 expression in mouse embryos has provided important clues to the understanding of the pathogenesis
of Aarskog–Scott syndrome.
It appears likely that the primary defect in Aarskog–Scott syndrome is an abnormality of FGD1/Cdc42 signaling resulting in anomalous embryonic development and abnormal endochondral and intramembranous bone formation.
may be available for mutations in the FGDY1 gene. Genetic counseling
is indicated for individuals or families who may carry this condition, as there are overlapping features with Fetal alcohol syndrome
.
may be required to correct some of the anomalies, and orthodontic treatment may be used to correct some of the facial abnormalities. Trials of growth hormone
have not been effective to treat short stature in this disorder.
Some recent findings have included cystic changes in the brain and generalized seizure
s . There may be difficulty growing in the first year of life in up to one-third of cases. Misaligned teeth may require orthodontic correction. An undescended testicle will require surgery.
Adenylosuccinate lyase deficiency (MIM 103050, ADSL) is a rare autosomal recessive disease causing severe mental retardation and/or autistic features.1,2 Seizures are often observed (80%),3 varying in age of onset (from newborn to late childhood) and nature (tonic-clonic, “suppression burst” pattern, West syndrome, etc.), and are very often resistant to all medication. Around 50% of the children show autistic-like behaviour.4 Microcephaly is rare (1/13 of reported cases). Non-specific anomalies of the brain, such as hypoplasia of the vermis, cerebral atrophy,5 lack of myelination,6 white matter anomalies,7 and lissencephaly4 have often been described.
Other Complications: • Low self-esteem • Social difficulties related to physical problems • Male infertility in those with both testes undescended • Problems with the structure of the heart • Accumulation of fluid in tissues of body (lymphedema, cystic hygroma) • Failure to thrive in infants.
Short stature
Short stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...
, facial abnormalities, skeletal and genital anomalies.
The Aarskog–Scott syndrome (AAS) is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia.
Signs and symptoms
The Aarskog–Scott syndrome is a disorder with short stature, hypertelorismHypertelorism
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
, downslanting palpebral fissure
Palpebral fissure
Palpebral fissure is the anatomic name for the separation between the upper and lower eyelids. In adults, this measures about 10mm vertically and 30mm horizontally.It can be reduced in horizontal size by fetal alcohol syndrome and in Williams Syndrome...
s, anteverted nostrils, joint laxity, shawl scrotum, and mental retardation. The physical phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
varies with age and postpuberal males may have only minor remnant manifestations of the prepuberal phenotype.
- Growth
- mild to moderate short stature evident by 1–3 years of age
- delayed adolescent growth spurt
- Performance
- slight (dull normal) to moderate mental deficiency
- hyperactivity and attention deficit
- social performance usually good
- Face
- rounded face
- widow's peakWidow's peakA widow's peak is a distinct point in the hairline in the center of the forehead. This hair anomaly is a result of a lower-than-usual position of the intersection of the bilateral periorbital fields of hair-growth suppression on the forehead.-Definition:...
hairline - wide-set eyes (hypertelorismHypertelorismHypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
) - droopy eyelids (blepharoptosis)
- downslanting eye slits (palpebral fissurePalpebral fissurePalpebral fissure is the anatomic name for the separation between the upper and lower eyelids. In adults, this measures about 10mm vertically and 30mm horizontally.It can be reduced in horizontal size by fetal alcohol syndrome and in Williams Syndrome...
s) - small nose with nostrils tipped forward (anteverted)
- underdeveloped mid-portion of the face (maxillaMaxillaThe maxilla is a fusion of two bones along the palatal fissure that form the upper jaw. This is similar to the mandible , which is also a fusion of two halves at the mental symphysis. Sometimes The maxilla (plural: maxillae) is a fusion of two bones along the palatal fissure that form the upper...
) - wide groove above the upper lip (broad philtrumPhiltrumThe philtrum , is a medial cleft common to many mammals, extending from the nose to the upper lip, and, together with a glandular rhinarium and slit-like nostrils, is believed to constitute the primitive condition for mammals in general...
) - crease below the lower lip
- delayed eruption of teeth
- top portion (upper helix) of the ear folded over slightly
- Hands and feet
- small, broad hands and feet
- short fingers and toes (brachydactylyBrachydactylyBrachydactyly , is a medical term which literally means "shortness of the fingers and toes" . The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an inherited, usually dominant trait...
) - in-curving of the 5th finger (clinodactyly)
- mild interdigital webbingInterdigital webbingInterdigital webbing is the presence of membranes of skin between the digits. Normally in mammals, webbing is present in the embryo but resorbed later in development, but in various mammal species it occasionally persists in adulthood...
, between fingers as well as toes - single transverse "simian creaseSimian creaseIn humans, a single transverse palmar crease is a single crease that extends across the palm of the hand, formed by the fusion of the two palmar creases that people typically have...
" in palm - broad thumbs and big toes
- Neck
- short neck
- webbing of sides of the neck
- Chest
- mild pectus excavatumPectus excavatumPectus excavatum is the most common congenital deformity of the anterior wall of the chest, in which several ribs and the sternum grow abnormally. This produces a caved-in or sunken appearance of the chest...
(sunken chest)
- mild pectus excavatum
- Abdomen
- protruding navelNavelThe navel is a scar on the abdomen caused when the umbilical cord is removed from a newborn baby...
- inguinal herniaInguinal herniaAn inguinal hernia is a protrusion of abdominal-cavity contents through the inguinal canal. They are very common , and their repair is one of the most frequently performed surgical operations....
s
- protruding navel
- Genitalia
- Shawl ScrotumShawl scrotumShawl scrotum is a condition in which the scrotum surrounds the penis, resembling a 'shawl'.It is a characteristic of some syndromes such as Aarskog-Scott syndrome , Rubenstein-Taybi syndrome, craniofrontonasal dysplasia, Hunter Carpenter McDonald Syndrome, Naguib Syndrome, Saito Kuba Tsuruta...
- undescended testiclesCryptorchidismCryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
- Shawl Scrotum
Genetics
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
manner. The sons of female carriers are at 50% risk of being affected with the syndrome. The daughters of female carriers are at 50% risk of being carriers themselves. Females may have mild manifestations of the syndrome. The syndrome is caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
called FGDY1 in band p11.21 on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
.
Pathophysiology
The Aarskog–Scott syndrome is due to mutation in the FGD1FGD1
FYVE, RhoGEF and PH domain-containing protein 1 also known as faciogenital dysplasia 1 protein , zinc finger FYVE domain-containing protein 3 , or Rho/Rac guanine nucleotide exchange factor FGD1 is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome...
gene. FGD1 encodes a guanine nucleotide exchange factor
Guanine nucleotide exchange factor
Guanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...
(GEF) that specifically activates Cdc42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
, a member of the Rho (Ras homology) family of the p21 GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
s. By activating Cdc42, FGD1 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
stimulates fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s to form filopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 protein also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, and cellular differentiation.
Within the developing mouse skeleton, FGD1 protein is expressed in precartilaginous mesenchymal condensations, the perichondrium
Perichondrium
The perichondrium is a layer of dense irregular connective tissue which surrounds the cartilage of developing bone. It consists of two separate layers: an outer fibrous layer and inner chondrogenic layer. The fibrous layer contains fibroblasts, which produce collagenous fibers. The chondrogenic...
and periosteum, proliferating chondrocyte
Chondrocyte
Chondrocytes are the only cells found in cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans...
s, and osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
s. These results suggest that FGD1 signaling may play a role in the biology of several different skeletal cell types including mesenchymal prechondrocytes, chondrocytes, and osteoblasts. The characterization of the spatiotemporal pattern of FGD1 expression in mouse embryos has provided important clues to the understanding of the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of Aarskog–Scott syndrome.
It appears likely that the primary defect in Aarskog–Scott syndrome is an abnormality of FGD1/Cdc42 signaling resulting in anomalous embryonic development and abnormal endochondral and intramembranous bone formation.
Diagnosis
Genetic testingGenetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
may be available for mutations in the FGDY1 gene. Genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
is indicated for individuals or families who may carry this condition, as there are overlapping features with Fetal alcohol syndrome
Fetal alcohol syndrome
Fetal alcohol syndrome is a pattern of mental and physical defects that can develop in a fetus in association with high levels of alcohol consumption during pregnancy. Current research also implicates other lifestyle choices made by the prospective mother...
.
Treatment
SurgerySurgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
may be required to correct some of the anomalies, and orthodontic treatment may be used to correct some of the facial abnormalities. Trials of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
have not been effective to treat short stature in this disorder.
Prognosis
Mild degrees of mental slowness may be present, but affected children usually have good social skills. Some males may exhibit reduced fertility.Some recent findings have included cystic changes in the brain and generalized seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s . There may be difficulty growing in the first year of life in up to one-third of cases. Misaligned teeth may require orthodontic correction. An undescended testicle will require surgery.
Adenylosuccinate lyase deficiency (MIM 103050, ADSL) is a rare autosomal recessive disease causing severe mental retardation and/or autistic features.1,2 Seizures are often observed (80%),3 varying in age of onset (from newborn to late childhood) and nature (tonic-clonic, “suppression burst” pattern, West syndrome, etc.), and are very often resistant to all medication. Around 50% of the children show autistic-like behaviour.4 Microcephaly is rare (1/13 of reported cases). Non-specific anomalies of the brain, such as hypoplasia of the vermis, cerebral atrophy,5 lack of myelination,6 white matter anomalies,7 and lissencephaly4 have often been described.
Other Complications: • Low self-esteem • Social difficulties related to physical problems • Male infertility in those with both testes undescended • Problems with the structure of the heart • Accumulation of fluid in tissues of body (lymphedema, cystic hygroma) • Failure to thrive in infants.
History
The syndrome is named for Dagfinn Aarskog, a Norwegian pediatrician and human geneticist who first described it in 1970, and for Charles I. Scott, Jr., an American medical geneticist who independently described the syndrome in 1971.External links
- Aarskog syndrome (Aarskog-Scott syndrome), detailed up-to-date information in OMIM (PediaBook.com)
- Faciogenital Dysplasia (Aarskog-Scott syndrome), detailed up-to-date information in OMIM (Online Mendelian Inheritance in Man)
- Images of clinical features of Aarskog-Scott syndrome
- Pediatric Database Pedbase