Aarskog-Scott syndrome

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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).[1]
  • 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.[2]
  • In 1978, Escobar and Weaver described a patient who is had symptoms of Noonan syndrome than Aarskog-Scott syndrome (AAS).[3]
  • In 1981, Grier et al. suggested that Aarskog-Scott syndrome (AAS) follows autosomal dominant pattern of inheritance.[4]
  • 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.[5]
  • In 1994, Fernandez et al. mentioned 10 Japanese patients who are positive with Aarskog syndrome.[6]
  • In 1998, Logie and Porteous concluded that in patients with Aarskog-Scott syndrome (AAS) have normal intelligence.[7]
  • In 2002, Lebel et al. is the one who found a missense mutation in the FGD1 gene.[8]
  • In 2005, Orrico et al. described attention deficit-hyperactivity disorder (ADHD) in patient with Aarskog-Scott syndrome (AAS).[9]
  • In 2010, Orrico et al. genetically confirmed 11 patients for Aarskog-Scott syndrome.[10]

Classification

  • There is no established system for the classification of Aarskog-Scott syndrome (AAS).[11]

Pathophysiology

Causes

Genetic Cause

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

Differentiating Aarskog-Scott syndrome from other Diseases

Epidemiology and Demographics

Incidence

  • The incidence of Aarskog-Scott syndrome (AAS) is unknown.[34]
  • 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.[35]
  • 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.[36]

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

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:[40][41][42]
Aarskog syndrome
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[43]

History and Symptoms

Common Symptoms

Common symptoms of Aarskog-Scott syndrome (AAS) include:[24][44]

Physical Examination

HEENT

Facial features are very prominent and important for the diagnosis of Aarskog-Scott syndrome (AAS) which include:[45][46][47][48]

Neck

Chest

Abdomen

Genitourinary

Extremities

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

  • 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:[49]

Echocardiography and Ultrasound

  • The ultrasound can help in detecting the undescended testis associated with Aarskog-Scott syndrome (AAS).[50]

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:

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.[51][52]

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

Primary Prevention

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

Secondary Prevention

References

  1. ↑ Scott CI (1971). "Unusual facies, joint hypermobility, genital anomaly and short stature: a new dysmorphic syndrome". Birth Defects Orig Artic Ser. 7 (6): 240–6. PMID 5173168.
  2. ↑ Grier RE, Farrington FH, Kendig R, Mamunes P (1983). "Autosomal dominant inheritance of the Aarskog syndrome". Am J Med Genet. 15 (1): 39–46. doi:10.1002/ajmg.1320150105. PMID 6344635.
  3. ↑ Escobar V, Weaver DD (1978). "Aarskog syndrome. New findings and genetic analysis". JAMA. 240 (24): 2638–41. doi:10.1001/jama.240.24.2638. PMID 712980.
  4. ↑ Grier, Robert E.; Farrington, Frank H.; Kendig, Robert; Mamunes, Peter; Opitz, John M. (1983). "Autosomal dominant inheritance of the Aarskog syndrome". American Journal of Medical Genetics. 15 (1): 39–46. doi:10.1002/ajmg.1320150105. ISSN 0148-7299.
  5. ↑ van den Bergh P, Fryns JP, Wilms G, Piot R, Dralands G, van den Bergh R (1984). "Anomalous cerebral venous drainage in Aarskog syndrome". Clin Genet. 25 (3): 288–94. doi:10.1111/j.1399-0004.1984.tb01991.x. PMID 6705262.
  6. ↑ Fernandez I, Tsukahara M, Mito H, Yoshii H, Uchida M, Matsuo K; et al. (1994). "Congenital heart defects in Aarskog syndrome". Am J Med Genet. 50 (4): 318–22. doi:10.1002/ajmg.1320500404. PMID 8209909.
  7. ↑ Logie LJ, Porteous ME (1998). "Intelligence and development in Aarskog syndrome". Arch Dis Child. 79 (4): 359–60. doi:10.1136/adc.79.4.359. PMC 1717704. PMID 9875050.
  8. ↑ Lebel RR, May M, Pouls S, Lubs HA, Stevenson RE, Schwartz CE (2002). "Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene". Clin Genet. 61 (2): 139–45. doi:10.1034/j.1399-0004.2002.610209.x. PMID 11940089.
  9. ↑ Orrico A, Galli L, Buoni S, Hayek G, Luchetti A, Lorenzini S; et al. (2005). "Attention-deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog-Scott syndrome due to a novel FGD1 gene mutation (R408Q)". Am J Med Genet A. 135 (1): 99–102. doi:10.1002/ajmg.a.30700. PMID 15809997.
  10. ↑ Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, Hertz JM; et al. (2010). "Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene". Am J Med Genet A. 152A (2): 313–8. doi:10.1002/ajmg.a.33199. PMID 20082460.
  11. ↑ Estrada L, Caron E, Gorski JL (2001). "Fgd1, the Cdc42 guanine nucleotide exchange factor responsible for faciogenital dysplasia, is localized to the subcortical actin cytoskeleton and Golgi membrane". Hum Mol Genet. 10 (5): 485–95. doi:10.1093/hmg/10.5.485. PMID 11181572.
  12. ↑ Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, Stevenson RE; et al. (1994). "Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor". Cell. 79 (4): 669–78. doi:10.1016/0092-8674(94)90552-5. PMID 7954831.
  13. ↑ Pasteris NG, Buckler J, Cadle AB, Gorski JL (1997). "Genomic organization of the faciogenital dysplasia (FGD1; Aarskog syndrome) gene". Genomics. 43 (3): 390–4. doi:10.1006/geno.1997.4837. PMID 9268645.
  14. ↑ Aarskog D (1971). "A familial syndrome of short stature associated with facial dysplasia and genital anomalies". Birth Defects Orig Artic Ser. 7 (6): 235–9. PMID 4155960.
  15. ↑ Grier RE, Farrington FH, Kendig R, Mamunes P (1983). "Autosomal dominant inheritance of the Aarskog syndrome". Am J Med Genet. 15 (1): 39–46. doi:10.1002/ajmg.1320150105. PMID 6344635.
  16. ↑ Bawle, E.; Tyrkus, M.; Lipman, S.; Bozimowski, D.; Opitz, John M. (1984). "Aarskog syndrome: Full male and female expression associated with an X-autosome translocation". American Journal of Medical Genetics. 17 (3): 595–602. doi:10.1002/ajmg.1320170307. ISSN 0148-7299.
  17. ↑ Zou, Weiguo; Greenblatt, Matthew B.; Shim, Jae-Hyuck; Kant, Shashi; Zhai, Bo; Lotinun, Sutada; Brady, Nicholas; Hu, Dorothy Zhang; Gygi, Steven P.; Baron, Roland; Davis, Roger J.; Jones, Dallas; Glimcher, Laurie H. (2011). "MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice". Journal of Clinical Investigation. 121 (11): 4383–4392. doi:10.1172/JCI59041. ISSN 0021-9738.
  18. ↑ Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns JP, Crushell E; et al. (2004). "Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients". Eur J Hum Genet. 12 (1): 16–23. doi:10.1038/sj.ejhg.5201081. PMID 14560308.
  19. ↑ Pedigo NG, Van Delden D, Walters L, Farrell CL (2016). "Minireview: Role of genetic changes of faciogenital dysplasia protein 1 in human disease". Physiol Genomics. 48 (7): 446–54. doi:10.1152/physiolgenomics.00101.2015. PMID 27199457.
  20. ↑ Pasteris NG, Nagata K, Hall A, Gorski JL (2000). "Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue". Gene. 242 (1–2): 237–47. doi:10.1016/s0378-1119(99)00518-1. PMID 10721717.
  21. ↑ Rajnicek AM, Foubister LE, McCaig CD (2006). "Temporally and spatially coordinated roles for Rho, Rac, Cdc42 and their effectors in growth cone guidance by a physiological electric field". J Cell Sci. 119 (Pt 9): 1723–35. doi:10.1242/jcs.02896. PMID 16595546.
  22. ↑ Pasteris NG, Gorski JL (1999). "Isolation, characterization, and mapping of the mouse and human Fgd2 genes, faciogenital dysplasia (FGD1; Aarskog syndrome) gene homologues". Genomics. 60 (1): 57–66. doi:10.1006/geno.1999.5903. PMID 10458911.
  23. ↑ Orrico A, Galli L, Falciani M, Bracci M, Cavaliere ML, Rinaldi MM; et al. (2000). "A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome)". FEBS Lett. 478 (3): 216–20. doi:10.1016/s0014-5793(00)01857-3. PMID 10930571.
  24. ↑ 24.0 24.1 Schwartz CE, Gillessen-Kaesbach G, May M, Cappa M, Gorski J, Steindl K; et al. (2000). "Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome". Eur J Hum Genet. 8 (11): 869–74. doi:10.1038/sj.ejhg.5200553. PMID 11093277.
  25. ↑ Pasteris NG, Buckler J, Cadle AB, Gorski JL (1997). "Genomic organization of the faciogenital dysplasia (FGD1; Aarskog syndrome) gene". Genomics. 43 (3): 390–4. doi:10.1006/geno.1997.4837. PMID 9268645.
  26. ↑ Hall A (2005). "Rho GTPases and the control of cell behaviour". Biochem Soc Trans. 33 (Pt 5): 891–5. doi:10.1042/BST20050891. PMID 16246005.
  27. ↑ Ridley AJ, Allen WE, Peppelenbosch M, Jones GE (1999). "Rho family proteins and cell migration". Biochem Soc Symp. 65: 111–23. PMID 10320936.
  28. ↑ Linseman DA, Laessig T, Meintzer MK, McClure M, Barth H, Aktories K; et al. (2001). "An essential role for Rac/Cdc42 GTPases in cerebellar granule neuron survival". J Biol Chem. 276 (42): 39123–31. doi:10.1074/jbc.M103959200. PMID 11509562.
  29. ↑ Bishop AL, Hall A (2000). "Rho GTPases and their effector proteins". Biochem J. 348 Pt 2: 241–55. PMC 1221060. PMID 10816416.
  30. ↑ Orrico, A.; Galli, L.; Faivre, L.; Clayton-Smith, J.; Azzarello-Burri, S.M.; Hertz, J.M.; Jacquemont, S.; Taurisano, R.; Arroyo Carrera, I.; Tarantino, E.; Devriendt, K.; Melis, D.; Thelle, T.; Meinhardt, U.; Sorrentino, V. (2010). "Aarskog-Scott syndrome: Clinical update and report of nine novel mutations of theFGD1gene". American Journal of Medical Genetics Part A. 152A (2): 313–318. doi:10.1002/ajmg.a.33199. ISSN 1552-4825.
  31. ↑ Parıltay E, Hazan F, Ataman E, Demir K, Etlik Ö, Özbek E; et al. (2016). "A novel splice site mutation of FGD1 gene in an Aarskog-Scott syndrome patient with a large anterior fontanel". J Pediatr Endocrinol Metab. 29 (9): 1111–4. doi:10.1515/jpem-2015-0482. PMID 27544718.
  32. ↑ Weinstein, Lee S. (2016). "GNAS and McCune-Albright/Fibrous Dysplasia, Albright Hereditary Osteodystrophy, and Pseudohypoparathyroidism": 1178–1181. doi:10.1093/med/9780199934522.003.0179.
  33. ↑ Reza Jabalameli, M.; Briceno, Ignacio; Martinez, Julio; Briceno, Ignacio; J. Pengelly, Reuben; Ennis, Sarah; Collins, Andrew (2016). "Aarskog-Scott syndrome: phenotypic and genetic heterogeneity". AIMS Genetics. 3 (1): 49–59. doi:10.3934/genet.2016.1.49. ISSN 2377-1143.
  34. ↑ Reza Jabalameli, M.; Briceno, Ignacio; Martinez, Julio; Briceno, Ignacio; J. Pengelly, Reuben; Ennis, Sarah; Collins, Andrew (2016). "Aarskog-Scott syndrome: phenotypic and genetic heterogeneity". AIMS Genetics. 3 (1): 49–59. doi:10.3934/genet.2016.1.49. ISSN 2377-1143.
  35. ↑ Orrico A, Galli L, Clayton-Smith J, Fryns JP (2015) Clinical utility gene card for: Aarskog-Scott Syndrome (faciogenital dysplasia) - update 2015. Eur J Hum Genet 23 (4):. DOI:10.1038/ejhg.2014.178 PMID: 25227149
  36. ↑ Reza Jabalameli, M.; Briceno, Ignacio; Martinez, Julio; Briceno, Ignacio; J. Pengelly, Reuben; Ennis, Sarah; Collins, Andrew (2016). "Aarskog-Scott syndrome: phenotypic and genetic heterogeneity". AIMS Genetics. 3 (1): 49–59. doi:10.3934/genet.2016.1.49. ISSN 2377-1143.
  37. ↑ Jogiya, Aryan; Sandy, Charles (2009). "Mild Optic Nerve Hypoplasia with Retinal Venous Tortuosity in Aarskog (Facial-Digital-Genital) Syndrome". Ophthalmic Genetics. 26 (3): 139–141. doi:10.1080/13816810500229025. ISSN 1381-6810.
  38. ↑ Pizio HF, Scott MH, Richard JM (1994). "Tortuosity of the retinal vessels in Aarskog syndrome (faciogenital dysplasia)". Ophthalmic Genet. 15 (1): 37–40. PMID 7953251.
  39. ↑ Grier RE, Farrington FH, Kendig R, Mamunes P (1983). "Autosomal dominant inheritance of the Aarskog syndrome". Am J Med Genet. 15 (1): 39–46. doi:10.1002/ajmg.1320150105. PMID 6344635.
  40. ↑ Grier RE, Farrington FH, Kendig R, Mamunes P (1983). "Autosomal dominant inheritance of the Aarskog syndrome". Am J Med Genet. 15 (1): 39–46. doi:10.1002/ajmg.1320150105. PMID 6344635.
  41. ↑ Darendeliler F, Larsson P, Neyzi O, Price AD, Hagenäs L, Sipilä I; et al. (2003). "Growth hormone treatment in Aarskog syndrome: analysis of the KIGS (Pharmacia International Growth Database) data". J Pediatr Endocrinol Metab. 16 (8): 1137–42. PMID 14594174.
  42. ↑ Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns JP, Crushell E; et al. (2004). "Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients". Eur J Hum Genet. 12 (1): 16–23. doi:10.1038/sj.ejhg.5201081. PMID 14560308.
  43. ↑ "Identification of novel mutations in Mexican patients with Aarskog–Scott syndrome".
  44. ↑ Şıklar Z, Berberoğlu M (2014). "Syndromic disorders with short stature". J Clin Res Pediatr Endocrinol. 6 (1): 1–8. doi:10.4274/Jcrpe.1149. PMC 3986733. PMID 24637303.
  45. ↑ Reza Jabalameli, M.; Briceno, Ignacio; Martinez, Julio; Briceno, Ignacio; J. Pengelly, Reuben; Ennis, Sarah; Collins, Andrew (2016). "Aarskog-Scott syndrome: phenotypic and genetic heterogeneity". AIMS Genetics. 3 (1): 49–59. doi:10.3934/genet.2016.1.49. ISSN 2377-1143.
  46. ↑ Bedoyan JK, Friez MJ, DuPont B, Ahmad A (2009). "First case of deletion of the faciogenital dysplasia 1 (FGD1) gene in a patient with Aarskog-Scott syndrome". Eur J Med Genet. 52 (4): 262–4. doi:10.1016/j.ejmg.2008.12.001. PMID 19110080.
  47. ↑ Teebi AS, Rucquoi JK, Meyn MS (1993). "Aarskog syndrome: report of a family with review and discussion of nosology". Am J Med Genet. 46 (5): 501–9. doi:10.1002/ajmg.1320460508. PMID 8322809.
  48. ↑ Ulaş, Cıkla; Giampietro, Philip F.; Sadighi, Alireza; Başkaya, Mustafa K. (2014). "Ruptured Posterior Communicating Artery Aneurysm Associated with Aarskog Syndrome". NMC Case Report Journal. 2 (3): 85–87. doi:10.2176/nmccrj.2014-0022. ISSN 2188-4226.
  49. ↑ Sariyilmaz K, Ozkunt O, Korkmaz M, Dikici F, Domanic U (2017). "Aarskog-Scott syndrome: An unusual cause of scoliosis". J Craniovertebr Junction Spine. 8 (3): 283–284. doi:10.4103/jcvjs.JCVJS_133_16. PMC 5634118. PMID 29021683.
  50. ↑ Tasian GE, Copp HL, Baskin LS (2011). "Diagnostic imaging in cryptorchidism: utility, indications, and effectiveness". J Pediatr Surg. 46 (12): 2406–13. doi:10.1016/j.jpedsurg.2011.08.008. PMC 3712862. PMID 22152893.
  51. ↑ Deodati A, Cianfarani S (2017). "The Rationale for Growth Hormone Therapy in Children with Short Stature". J Clin Res Pediatr Endocrinol. 9 (Suppl 2): 23–32. doi:10.4274/jcrpe.2017.S003. PMC 5790327. PMID 29280742.
  52. ↑ Frindik JP, Kemp SF (2010). "Managing idiopathic short stature: role of somatropin (rDNA origin) for injection". Biologics. 4: 147–55. PMC 2898102. PMID 20631818.

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