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.
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.
Entire Body System
- Single Transverse Palmar Crease
transverse palmar crease 0000954 Strabismus Cross-eyed Squint Squint eyes [ more ] 0000486 Talipes 0001883 1%-4% of people have these symptoms Broad philtrum 0000289 Global developmental delay 0001263 Intellectual disability, mild Mental retardation, [rarediseases.info.nih.gov]
Sporadic Symptoms Round face and a shorter neck, epicanthic folds, maxillary hypoplasia, which causes several facial abnormalities, and single transverse palmar crease may be seen in some patients. [news-medical.net]
- Failure to Thrive
Cardiac failure Cardiac failures Heart failure [ more ] 0001635 Delayed eruption of teeth Delayed eruption Delayed teeth eruption Delayed tooth eruption Eruption, delayed Late eruption of teeth Late tooth eruption [ more ] 0000684 Epicanthus Eye folds [rarediseases.info.nih.gov]
Intellectual Disabilities Hyperactivity Weight gain failure Failure to thrive Chronic respiratory infections Other Symptoms Congenital heart defects Scoliosis Extra ribs Cleft palate/ lip Mild webbing of the fingers Short neck with or without webbing [medcaretips.com]
Some cases might also show failure to thrive, which is typically coupled with the development of chronic respiratory infections. [symptoma.com]
Face, Head & Neck
She exhibited ocular hypertelorism (Figure-1), up-slanting palpebral fissures, malar hypoplasia, anteverted nostrils, slight retrognathia, clinodactyly of the fifth fingers and joint hyperextensibility. [scielo.br]
As previously reported, 6 carrier females often show minor dysmorphic features such as hypertelorism and widow's peak. [doi.org]
Ophthalmic findings include a slight downward slant to the palpebral fissures, hypertelorism, blepharoptosis, strabismus, ophthalmoplegia, hypermetropic astigmatism and a large cornea. [ncbi.nlm.nih.gov]
- Round Face
Individuals with the Aarskog syndrome have shortness of stature, round face, hypertelorism, short fingers and hands, and flat feet; males have a shawl scrotum. [ncbi.nlm.nih.gov]
Rounded face. Impaired development of the mid section of the face. Wide set of eyes. Hairline resembling the peak of a widow. Crease below the lower lip. Droopy eyelids. Small nose with nostrils tripped forward. [primehealthchannel.com]
Characteristic features include a round face with a broad forehead, a broad nasal bridge with a short stubby nose and anteverted nostrils, hypertelorism, and a shawl (saddlebag) scrotum. [whonamedit.com]
[…] disorder Attention deficit Attention deficit disorder Attention deficit-hyperactivity disorder Attention deficits Childhood attention deficit/hyperactivity disorder [ more ] 0007018 Cleft palate Cleft roof of mouth 0000175 Cleft upper lip Harelip 0000204 [rarediseases.info.nih.gov]
Hyperactive behavior and symptoms of attention deficit disorders were frequently observed (61% of the mentally normal and 84% of the mentally subnormal), but regressed completely after the age of 12 to 14 years. [ncbi.nlm.nih.gov]
Inability to concentrate and hyperactivity. Facial Abnormalities Delayed formation of teeth. Downward slant of the eye slits. Rounded face. Impaired development of the mid section of the face. Wide set of eyes. [primehealthchannel.com]
Both patients were found to suffer developmental delay, aggressive behavior and hyperactivity. [bmcpediatr.biomedcentral.com]
At present, he is of low normal intelligence (WISC-R scale: IQ 80) with impairment in expressive language and speech articulation difficulties, emotional behaviour problems with occasional temper tantrums, short stature (132.5 cm; 5th percentile), moderate [doi.org]
Aarskog syndrome is characterised by a disproportionately short stature and facial, skeletal and urogenital anomalies ('shawl' scrotum and cryptorchidism). [ncbi.nlm.nih.gov]
Genitourinary Manifestations 'shawl' scrotum (80%) cryptorchidism (75%) inguinal hernia (60%) 3. Ophthalmologic Manifestations hyperopic astigmatism large corneas ophthalmoplegia strabismus 4. [web.archive.org]
[…] brachydactyly interdigital webbing hypoplasia of the middle phalanges proximal interphalangeal joint laxity with concomitant flexion and restriction of movement of distal interphalangeal joints flat broad feet with bulbous toes genital anomalies shawl scrotum cryptorchidism [radiopaedia.org]
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.
- Delayed Bone Age
The main findings are asynchronic and delayed bone age, shortened long tubular bones with wide metaphyses, brachyphalangy, hypoplasia of the middle phalanges of the fifth fingers, short and broad first metacarpals and metatarsals and pelvic hypoplasia [ncbi.nlm.nih.gov]
Other Manifestations delayed puberty mild pectus excavatum prominent umbilicus INVESTIGATIONS: 1. Imaging Studies 1. Skeletal X-Rays delayed bone age MANAGEMENT: 1. [web.archive.org]
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 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.
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 a congenital disorder, no prevention measures can be recommended at this stage.
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.
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.
- Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, Hertz JM, Jacquemont S, Taurisano R, Arroyo Carrera I, Tarantino E, Devriendt K, Melis D, Thelle T, Meinhardt U, Sorrentino V. Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene. Am. J. Med. Genet. 152A: 313-318, 2010.
- Aarskog D. A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J. Pediat. 77: 856-861, 1970.
- Scott CI. Unusual facies, joint hypermobility, genital anomaly and short stature: a new dysmorphic syndrome. Birth Defects Orig. Art. Ser. VII(6): 240-246, 1971.
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- Schwartz CE, Gillessen-Kaesbach G, May M, Cappa M, Gorski J, Steindl K, Neri G. Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome. Europ. J. Hum. Genet. 8: 869-874, 2000.
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- Fernandez I, Tsukahara M, Mito H, Yoshii H, Uchida M, Matsuo K, Kajii T. Congenital heart defects in Aarskog syndrome. Am. J. Med. Genet. 50: 318-322, 1994.
- Orrico A, Galli L, Clayton-Smith J, Fryns JP. Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015. Eur J Hum Genet. 2015 Apr;23(4).