Aarskog-Scott syndrome: Difference between revisions

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* Common complications of [disease name] include:
* Common complications of [disease name] include:
** [Complication 1]
** Cryptorchidism
** [Complication 2]
** Spina bifida occulta
** [Complication 3]
** Cervical spine abnormalities
**Scoliosis
**Camptodactyly
**Lymphoedema
**Optic nerve hypoplasia
**Retinal vessel tortuosity


=== Prognosis ===
=== Prognosis ===

Revision as of 14:01, 3 September 2019

Synonyms and Keywords: Aarskog disease, Aarskog-Scott syndrome, AAS, Faciodigitogenital syndrome, Faciogenital dysplasia, FGDY, Scott Aarskog syndrome

Aarskog-Scott syndrome
ICD-10 Q87.1
ICD-9 759.89
OMIM 100050
DiseasesDB 29329

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.
  • Till now there are less than 100 cases of Aarskog-Scott syndrome (AAS) had been diagnosed worldwide.

Prevalence

  • The prevalence of Aarskog-Scott syndrome (AAS) is 1/25 000 worldwide.[30]
  • 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.

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

  • Common complications of [disease name] include:
    • Cryptorchidism
    • Spina bifida occulta
    • Cervical spine abnormalities
    • Scoliosis
    • Camptodactyly
    • Lymphoedema
    • Optic nerve hypoplasia
    • Retinal vessel tortuosity

Prognosis

  • Prognosis is generally good with Aarskog-Scott syndrome (AAS) patients.

Diagnostic study of choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-Ray Findings

Echocardiography and Ultrasound

CT-Scan Findings

MRI Findings

Other Imaging Findings

Other Diagnostic Studies

Medical Therapy

Interventions

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Genetic

X-linked recessive inheritance.

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.

Eponym

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.

Description

The Aarskog-Scott syndrome is a disorder with short stature, hypertelorism, downslanting palpebral fissures, 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.

Frequent features

  • 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 peak hairline
    • wide-set eyes (hypertelorism)
    • droopy eyelids (blepharoptosis)
    • downslanting eye slits (palpebral fissures)
    • small nose with nostrils tipped forward (anteverted)
    • underdeveloped mid-portion of the face (maxilla
    • wide groove above the upper lip (broad philtrum)
    • 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 (brachydactyly)
    • in-curving of the 5th finger (clinodactyly)
    • mild webbing between the fingers and toes
    • single transverse "simian crease" in palm
    • broad thumbs and big toes
  • Neck
    • short neck
    • webbing of sides of the neck
  • Chest
  • Abdomen
  • Genitalia

Diagnosis

Genetic testing 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.

Treatment

Surgery 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.

Support Group

The MAGIC Foundation for Children's Growth is a support group for Aarskog-Scott syndrome and can be found at www.magicfoundation.org.

Prognosis

Mild degrees of mental slowness may be present, but affected children usually have good social skills. Some males may exhibit reduced fertility.

Complications

Some recent findings have included cystic changes in the brain and generalized seizures. 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.

Molecular biology

The Aarskog-Scott syndrome is due to mutation in the FGD1 gene. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates Cdc42, a member of the Rho (Ras homology) family of the p21 GTPases. By activating Cdc42, FGD1 protein stimulates fibroblasts 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 periostium, proliferating chondrocytes, and osteoblasts. 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

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. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ Ridley AJ, Allen WE, Peppelenbosch M, Jones GE (1999). "Rho family proteins and cell migration". Biochem Soc Symp. 65: 111–23. PMID 10320936.
  26. ↑ 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.
  27. ↑ Bishop AL, Hall A (2000). "Rho GTPases and their effector proteins". Biochem J. 348 Pt 2: 241–55. PMC 1221060. PMID 10816416.
  28. ↑ 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.
  29. ↑ Weinstein, Lee S. (2016). "GNAS and McCune-Albright/Fibrous Dysplasia, Albright Hereditary Osteodystrophy, and Pseudohypoparathyroidism": 1178–1181. doi:10.1093/med/9780199934522.003.0179.
  30. ↑ 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

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