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Last updated: April 07, 2020
Years published: 1989, 1990, 1994, 1995, 1996, 2003, 2004, 2007, 2009, 2012, 2017, 2020
NORD gratefully acknowledges Dr. Alfredo Orrico, Molecular Medicine and Genetics, Azienda Ospedaliera Universitaria Senese, Viale Bracci. Siena, and Clinical Genetics. USL SudEst. Misericordia Hospital. Grosseto, Italy, for assistance in the preparation of this report.
Aarskog syndrome is a rare genetic condition characterized by short stature and multiple facial, limb and genital abnormalities. Additionally, some types of cognitive disorders may occasionally be present. Up to now, the FGD1 gene on the X chromosome is the only gene known to be associated with Aarskog syndrome.
Aarskog syndrome primarily affects males. Affected boys exhibit a characteristic set of facial, skeletal, and genital abnormalities. Clinical signs may vary from person to person (clinical heterogeneity), even within families. Males with Aarskog syndrome often have a rounded face with a broad forehead. Additional characteristic facial features include widely spaced eyes (ocular hypertelorism), drooping (ptosis) of the eyelids, downwardly slanting eyelid folds (palpebral fissures), a small nose with nostrils that are flared forward (anteverted nares), an underdeveloped upper jawbone (maxilliary hypoplasia), and a widowโs peak. Affected individuals may also have an abnormally long groove in the upper lip (philtrum) and a broad nasal bridge.
These children may also have a variety of abnormalities affecting the ears and teeth. Ear abnormalities include low-set ears and thickened, โfleshyโ earlobes. Dental abnormalities include missing teeth at birth, delayed eruption of teeth, and underdevelopment of the hard outer covering of teeth (enamel hypoplasia).
Aarskog syndrome is basically a skeletal dysplasia and affected males develop characteristic malformations of the skeletal system including disproportionate short stature; broad, short hands and feet; short, stubby fingers (brachydactyly) with permanent fixation of the fifth fingers in a bent position (clinodactyly); abnormally extendible finger joints; and wide flat feet with bulbous toes. In addition, affected individuals may have a sunken chest (pectus excavatum), protrusion of portions of the large intestine through an abnormal opening in the muscular lining of the abdominal cavity (inguinal hernia), and a prominent navel (umbilicus). Individuals with Aarskog syndrome may have spinal abnormalities such as incomplete closure of the bones of the spinal column (spina bifida occulta), fusion of the upper bones of the spinal column (cervical vertebrae), and underdevelopment of the โpeg-likeโ projection of the second cervical vertebra (odontoid hypoplasia).
Signs that help to make a diagnosis in males with Aarskog syndrome are the genital abnormalities, including a characteristic abnormal fold of skin extending around the base of the penis (โshawlโ scrotum) and/or failure of one or both of the testes to descend into the scrotum (cryptorchidism). In addition, the urinary opening (meatus) may be located on the underside of the penis (hypospadias) and the scrotum may appear clefted or divided (bifid scrotum).
Intellectual disability has been described in some affected boys but it is not a consistent feature of the disorder. Affected individuals may present with a range of mild learning difficulty and/or behavioral disorders: affected children may exhibit developmental delay during infancy, hyperactivity, attention deficit, impulsivity and opposition. Due to this possible spectrum of characteristics, the condition is also referred to as an ADHD syndromic disorder (MRXS16). Failure to gain weight and grow at the expected rate (failure to thrive) and development of chronic respiratory infections have also been described.
An additional spectrum of signs and/or symptoms may occur less frequently, including congenital heart defects; abnormal side-to-side curvature of the spine (scoliosis); additional pairs of ribs; incomplete closure of the roof of the mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip); mild webbing of the fingers; and a short neck with or without webbing. Additional eye abnormalities may be present including crossed eyes (strabismus), farsightedness (hyperopia), and paralysis of certain eye muscles (ophthalmoplegia). Some patients have been reported to have a tendency to be overweight.
Although Aarskog syndrome is a clinically and genetically heterogeneous condition, the best characterized form of the disorder is inherited as an X-linked trait and caused by changes (mutations) in the FGD1 gene. Aarskog syndrome primarily affects males. However, females who carry a single copy of a FGD1 gene mutation (heterozygotes) may exhibit some of the symptoms associated with the disorder. FGD1 gene mutations have been identified in approximately 22% of affected males; therefore, it is likely that other genes not yet identified may also be associated with this condition.
X-linked recessive genetic disorders are conditions caused by mutations in a gene located on the X chromosome. Females have two X chromosomes but one of the X chromosomes is โturned offโ to correct a dosage imbalance and almost all of the genes on that chromosome are silenced (inactivated) through a process defined as X-chromosome inactivation. Females who have a disease causing mutation on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is โsilencedโ. Males have one only X chromosome and, if they inherit the X chromosome that contains a disease gene, they will develop the disease. In turn, males with a X-linked disorder will pass the disease gene to all of their daughters, who will be carriers of the trait (obligate carriers). Males cannot pass X-linked traits to their sons because they always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter (like themselves), a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
Approximately 60 reports of Aarskog syndrome confirmed by identification of a FGD1 gene mutation have been published worldwide. However, it is possible that some mildly affected children may be unrecognized, making it difficult to determine the true frequency of this condition in the general population. An estimated population prevalence of Aarskog syndrome is equal to or slightly lower than to 1/25,000.
A diagnosis of Aarskog syndrome may be considered based upon a thorough clinical evaluation, a detailed patient and family history, and the identification of characteristic findings. Molecular genetic testing for FGD1 gene mutations is available to confirm the diagnosis. If a FGD1 gene mutation is not identified, molecular genetic testing for genes associated with similar conditions may be suggested, such as the ROR2 and WNT5A genes associated with Robinow syndrome.
The transition from the classic sequencing of single genes to protocols of next generation sequencing (NGS), recommends at least the use of panels that include, in addition to FGD1, the genes that cause overlapping conditions such as ROR2, WNT5A, PIK3R1, SRCAP, KMT2D, KDM6A, SHOX, CUL7.
Treatment
The treatment of Aarskog syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), eye specialists, and other health care professionals may need to systematically and comprehensively plan an affected childโs treatment.
Surgery may be necessary to treat specific congenital or structural malformations sometimes associated with Aarskog syndrome (hypospadias, inguinal or umbilical hernias, cryptorchidism, unusually severe craniofacial features). Individuals with Aarskog syndrome should receive complete eye and dental evaluations. Growth hormone treatment has been reported to improve height in some children, but confirmation is needed to determine appropriate management and expectations for response. For the possibly neurodevelopmental symptoms, a neuropsychiatric evaluation and input may be indicated. Other treatment is symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, the inheritance, and the recurrence risks of the condition in their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., visual handicaps, heart disease, etc.)
TEXTBOOKS
Gorski JL. Aarskog Syndrome. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins;2003:142.
Jones KL, ed. Smithโs Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co.;1997:128-29.
Gorlin RJ, Cohen MM Jr, Levin LS, eds. Syndromes of the Head and Neck. 3rd ed. London, UK: Oxford University Press; 990:295.
JOURNAL ARTICLES
Orrico A, Galli L, Clayton-Smith J and Fryns J-P: Clinical utility gene card for: AarskogโScott Syndrome (faciogenital dysplasia) โ update 2015. Eur J Hum Genet. 2015 Apr; 23(4).
Al-Semari A, Wakil SM, Al-Muhaizea MA et al: Novel FGD1 variant underlying Aarskog-Scott Syndrome with myopathy and distal arthropathy. Clin Dysmorphol. 2013;22:13โ17.
Verhoeven WM, Egger JI, Hoogeboom AJ: X-linked Aarskog syndrome: report on a novel FGD1 gene variant. Executive dysfunction as part of the behavioural phenotype. Genet Couns 2012;23:157โ167.
Pilozzi-Edmonds L1, Maher TA, Basran RK et al: Fraternal twins with Aarskog-Scott Syndrome due to maternal germline mosaicism. Am J Med Genet A 2011; 55A:1987โ1990.
Orrico A, Galli L, Faivre L et al: Aarskog-Scott Syndrome: clinical update and report of nine novel variants of the FGD1 gene. Am J Med Genet A 2010;152A:313โ318.
Bottani A, Orrico A, Galli L et al: Unilateral focal polymicrogyria in a patient with classical Aarskog-Scott Syndrome due to a novel missense variant in an evolutionary conserved RhoGEF domain of the faciogenital dysplasia gene FGD1. Am J Med Genet A 2007;143A:2334โ2338.
Orrico A, Galli L, Obregรณn MG, de Castro Perez MF, Falciani M, Sorrentino V: Unusually severe expression of craniofacial features in Aarskog-Scott Sรญndrome due to a novel truncating variant of the FDG1 gene. Am J Med Genet A 2007;143:58โ63.
Kaname T, Yanagi K, Okamoto N, Naritomi K: Neurobehavioral disorders in patients with Aarskog-Scott Syndrome affected by novel FGD1 variants. Am J Med Genet A 2006;140:1331โ1332.
Satoh M, Yokoya S: Anabolic steroid and gonadotropin releasing hormone analog combined treatment increased pubertal height gain and adult height in two children who entered puberty with short stature. J Pediatr Endocrinol Metab 2006;19:1125โ1131.
Shalev SA, Chervinski E, Weiner E, Mazor G, Friez MJ, Schwartz CE: Clinical variation of Aarskog syndrome in a large family with 2189delA in the FGD1 gene. Am J Med Genet A 2006;140:162โ165.
Orrico A, Galli L, Buoni S et al: Attention-deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog-Scott Syndrome due to a novel FGD1 gene variant (R408Q). Am J Med Genet A 2005;135:99โ102.
Orrico A, Galli L, Cavaliere ML et al: Phenotypic and molecular characterisation of the Aarskog syndrome: a survey of the clinical variability in light of FDG1 variant analysis in 46 patients. Eur J Hum Genet. 2004;12:16โ23.
Lebel RR, May M, Pouls S, Lubs HA, Stevenson RE, Schwartz CE: Non-syndromic X-linked mental retardation associated with a missense variant (P312L) in the FGD1 gene. Clin Genet. 2002;61:139โ145.
Schwartz CE, Gillessen-Kaesbach G, May M et al: Two novel variants confirm FDG1 is responsible for the Aarskog syndrome. Eur J Hum Genet 2000;8:869โ874.
Pasteris NG, Buckler J, Cadle AB, Gorski JL: Genomic organization of the faciogenital dysplasia (FGD1; Aarskog syndrome) gene. Genomics 1997;43:390โ394.
Fryns JP: Aarskog syndrome: the changing phenotype with age. Am J Med Genet. 1992;43:420โ427.
INTERNET
Aarskog syndrome. MedlinePlus. Review Date 10/26/2017. https://www.nlm.nih.gov/medlineplus/ency/article/001654.htm Accessed Feb 13, 2020.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. AARSKOG-SCOTT SYNDROME; AAS. Last edit date: 04/24/2013. https://www.omim.org/entry/305400 Accessed Feb 13, 2020.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. FYVE, RhoGEF, AND PH DOMAIN-CONTAINING PROTEIN 1; FGD1. Last edit date: 03/26/2012. https://www.omim.org/entry/300546 Accessed Feb 13, 2020.
ORPHANET. Aarskog-Scott sindrome. Last update: October 2012. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=394&Disease_Disease_Search_diseaseGroup=Aarskog-syndrome&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group of diseases=Aarskog-Scott-syndrome&title=Aarskog-Scott-syndrome&search=Disease_Search_Simple Accessed Feb 13, 2020.
Aarskog Syndrome. International Birth Defects Information Systems. Last Updated June 10, 2008. https://ibis-birthdefects.org/start/faciogen.htm Accessed Feb 13, 2020.
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NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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