Aarskog syndrome is a rare inherited disorder characterized by a series of anomalies on the face, limbs and genitals of the subjects concerned, whose short stature appears disproportionate and acromelic.
The major signs of this X-linked condition, also known as Aarskog-Scott syndrome or faciogenital dysplasia, are the already mentioned short stature , hypertelorism, shawl scrotum, and brachydactyly, all of them characterized by a wide phenotypic variability. Other typical features include joint hyperextensibility, short nose, window’s peak, and inguinal hernia, which can be integrated by the less frequent signs of mental retardation and other neurobehavioral aspects.
The syndrome was first described by Dagfinn Aarskog, a Norwegian pediatrician and human geneticist who studied the disorder in 1970, soon after followed by Charles L. Scott Jr., an American medical geneticist who also independently gave his fundamental contribution in the description of this condition with his research published in 1971. In particular, the work of Aarskog outlined the major signs of Aarskog syndrome, such as the ocular hypertelorism, the anteverted nostrils, and the distinctive penoscrotal anomalies , while that of Scott emphasized more the correlation with other less evident aspects such as hyperextensibility of fingers and toes or the hypermobility of the cervical spine . Because of the important contribution of these two scientists, the disorder now carries their names.
In the majority of the cases, Aarskog syndrome shows an X-linked recessive pattern of inheritance usually associated with the mutations in the FGD1 gene (faciogenital dysplasia 1 gene; Xp11.21) . However, the disorder appears clinically and genetically heterogeneous, with many cases based on genetic causes still not clearly defined, and this suggests the involvement of other yet unidentified genes in its etiology. For example, Pilozzi-Edmonds and her team, in their work published in 2011 , revealed a probable maternal germline mosaicism in the case of 2 fraternal twin brothers. The case was very much interesting, because the twins carried the same truncated form of the FGD1 gene, while the genetic analysis of the lymphocytes of their mother revealed that she did not have the same mutation. Particularly meaningful is also the work of Schwartz and his team in 2000, which detected a missense mutation as disorder-causing factor in a familial case of Aarskog syndrome and a deletion in a sporadic one . These results appear to suggest a much more complex genetic etiology of Aarskog syndrome, but further research needs to be done before reaching exhaustive final conclusions.
Since the data available are very limited, the prevalence of Aarskog syndrome is yet unknown. There are less than 100 cases present in the literature, with just 40 of which that have been molecularly proved. Measuring the real frequency of the disorder in the general population turns out to be even more difficult, since there are many mild cases going undetected due to their limited clinical evidence. In any case, experts estimate the prevalence of the disorder to be around 1 case every 25.000 people, in a condition which, because of its X-linked pattern of inheritance, predominantly affects male subjects.
FGD1 encodes for a guanine nucleotide exchange factor (GEF) which is involved in the activation of cdc42, a member of the Rho family of p21 GTPase. This protein plays a pivotal role in cell growth and communication, since it participates in the stimulation of fibroblasts to produce microspikes, important cytoskeleton elements implicated in cellular adhesion, migration, and signaling, and in the activation of c-jun N-terminal (JNK) kinase signaling cascade, an important biochemical pathway used by the cell to regulate its growth and differentiation. Furthermore, the tridimensional structure of FGD1 is characterized both by signaling proteins, like pleckstrin homology domain, and potential Src-homology 3 (SH3) binding sites, which might regulate the activity and location of this factor, aspects that can be seen as further confirmation of the important role played by FGD1 in cell growth and communication.
Many precious data are coming from the studies now being conducted in mouse embryos to characterize the FGD1 expression spatiotemporal patter during embryogenesis. These studies show how FGD1 is mainly expressed in skeletal cells such as mesenchymal prechondrocytes, chondrocytes, and osteoblasts, perhaps playing a pivotal role in their development. This seems to suggest the nature of the defect caused by the FGD1 mutations, which should be seen as the creation of an abnormal FGD1/cdc42 signaling that eventually provokes an anomalous embryonic development and the formation of endochondral and intramembranous bone elements.
Since Aarskog syndrome is an inherited disorder, no physical improvement can be seen in the life of those affected. However, from the point of view of mental capabilities, although the subjects usually show mental slowness in their early years, a good evolution can be seen in adulthood, with a visible improvement of their mental status in more advanced ages.
As previously said, Aarskog syndrome primarily affects males causing a set of abnormalities that mainly involve the face, skeleton and genitals of the subjects affected by it. The abnormalities involving the face include a rounded facial appearance with a broad forehead, a small nose with nostrils flaring forward (anteverted nares), an underdeveloped upper jawbone, and the so called widow’s peak, the characteristic central v-shaped point of the hairline. Eyes are heavily affected too, appearing widely separated (hypertelorism) with dropping eyelids (ptosis) and eyelid folds slanted downwardly. Less frequent, but no less characteristic, are also the unusually long groove of the upper lip (philtrum) and the broad nasal bridge . The single parts of the face, like ears and teeth, are affected by a variety of particular sub-abnormalities. The deformities affecting the ears might include, among the many other malformations, low-set ears and thickened “fleshy” earlobes, while those affecting the teeth might include delayed eruption of teeth or an unusual underdevelopment of their outer layer (enamel hypoplasia). The mouth also can be heavily affected, with an incomplete closure of its upper part (cleft palate). The eyes, instead, might show strabismus, hyperopia (farsightedness), or ophthalmoplegia (the paralysis of particular set of eye muscles).
On the other hand, the skeletal system malformations primarily consist of a disproportionate short stature, with abnormally extensible finger joints, a sunken chest (pectus excavatum) which sometime might show the presence of an additional pair of ribs, and short neck. Hands generally appear broad and short, with stubby fingers (brachydactyly) frequently coupled with the presence of fifth fingers permanently fixed in a bent position (clinodactyly), while feet appear wide and flat, with bulbous and squat toes. The 50% of affected individuals also show abnormalities interesting the spinal column, like the incomplete closure of the spinal bones (spina bifida occulta), the fusion of the upper spinal bones (cervical vertebrae), or abnormal lateral spinal curvature (scoliosis). Despite these skeletal abnormalities, the general size of the subjects at birth appear normal, at least until puberty, when the stature begins to acquire its characteristic short look because of the slowed growth rate.
The main feature of the genital abnormalities, instead, is represented by shawl scrotum, which is usually coupled with other deformities interesting the presence and the size of the testicle, like cryptorchidism and macroorchidism, or other less frequent malformations involving the urinary system like hypospadias.
Aarskog syndrome is also characterized by a mild intellectual disability, sometime associated with hyperactivity, although this cannot absolutely be considered as a consistent feature of this disorder  . Some cases might also show failure to thrive, which is typically coupled with the development of chronic respiratory infections. Other symptoms if Aarskog syndrome include congenital heart defects  and the presence of a mild webbing between fingers and toes.
The diagnosis of Aarskog syndrome is based on a comprehensive clinical examination, completed with a physical evaluation through X-rays studies. For a complete diagnostic valuation, it is important to get a detailed family history, seen as preparatory procedure for subsequent molecular genetic tests. The family history might confirm the typical X-linked inheritance pattern of Aarskog syndrome, which is undoubtedly the most frequent, but might also underline the presence of other types of inheritance, like an autosomal dominant or an autosomal recessive transmission, essential to detect the involvement of other key genes in the pathophysiology of the disorder through genetic counseling. In addition to the investigation of FGD1 gene, an approach for NGS using a panel of genes for syndromes evaluated in the differential diagnosis (eg. Robinow Syndrome) could be appropriate . Genetic tests can also be extremely useful in prenatal diagnosis, provided that the disease-causing mutation is known through previous family history studies.
Given the wide variability of its symptomatology, Aarskog syndrome treatments are usually patient-specific and primarily aimed at addressing the specific symptoms that each subject might show. The role would be to set up a team of specialists, like pediatricians, surgeons, cardiologists and speech pathologists, which through coordinated measures and efforts can organize an appropriate plan of action to face the physical abnormalities in a systematic and comprehensive manner. Since Aarskog syndrome is a congenital disorder, the majority of its treatments today still remain symptomatic and supportive.
Great hopes are now directed at a new strategy based on the clinical administration of growth hormones, which should be performed in the early phases of the patient’s life to prevent future physical malformations in adulthood. Unfortunately, the preliminary results of this strategy are still not clinically significant and required further research efforts to find a more effective clinical approach.
Since Aarskog syndrome is a congenital disorder, no prevention measures can be recommended at this stage.
Aarskog syndrome, also known as Aarskog-Scott syndrome (ASS) or faciogenital dysplasia, is a rare inherited disorder characterized by a series of anomalies on the face, limbs and genitals. The major signs of this X-linked condition are short stature, wide-set eyes (hypertelorism), shawl scrotum, and short fingers and toes (brachydactyly), all of them characterized by a wide phenotypic variability. Other typical features include joint hyperextensibility, short nose, window’s peak, and inguinal hernia, which can be integrated by the less frequent signs of mental retardation and other neurobehavioral aspects.
In the majority of the cases, Aarskog syndrome shows a X-linked recessive pattern of inheritance usually associated with the mutations in the FGD1 gene. The mutations in this gene have been associated with problems involving cell growth and communication, which might finally result in an abnormal embryonic development and the appearance of a abnormal physical structure .
Given the wide variability of its symptomatology, Aarskog syndrome treatments are usually patient-specific and primarily aimed at addressing the specific symptoms that each subject might show. The role would be to set up a team of specialists, like pediatricians, surgeons, cardiologists and speech pathologists, which through coordinated measures and efforts can organize an appropriate plan of action to face the physical abnormalities in a systematic and comprehensive manner. Since Aarskog syndrome is a congenital disorder, no prevention measures can be recommended at this stage.