Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 14921002; ICD10CM: Q87.19; ORPHA: 915; DO: 6683;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.22 | Intellectual developmental disorder, X-linked syndromic 16 | 305400 | X-linked recessive | 3 | FGD1 | 300546 |
| Xp11.22 | Aarskog-Scott syndrome | 305400 | X-linked recessive | 3 | FGD1 | 300546 |
A number sign (#) is used with this entry because Aarskog-Scott syndrome (AAS) can be caused by mutation in the FGD1 gene (300546) on chromosome Xp11.
Aarskog-Scott syndrome with attention deficit-hyperactivity disorder and a form of syndromic X-linked intellectual developmental disorder (MRXS16) are also caused by mutation in the FGD1 gene.
Aarskog-Scott syndrome, also known as faciogenital dysplasia, is an X-linked disorder characterized by short stature, hypertelorism, shawl scrotum, and brachydactyly, although there is wide phenotypic variability and other features, such as joint hyperextensibility, short nose, widow's peak (194000), and inguinal hernia, may also occur. Most patients do not have impaired intellectual development, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature (summary by Orrico et al., 2010).
Aarskog (1970) described an X-linked disorder characterized by embryonic ocular hypertelorism, anteverted nostrils, broad upper lip, and peculiar penoscrotal relations ('saddle-bag scrotum' or 'shawl scrotum'). Affected males can reproduce. Scott (1971) emphasized the occurrence of ligamentous laxity manifest by hyperextensibility of the fingers, genu recurvatum, and flat feet. Furthermore, hypermobility in the cervical spine with anomaly of the odontoid resulted in neurologic deficit. He studied a family with 9 affected males in 5 sibships.
Sugarman et al. (1973) described a Mexican-American family in which 2 half brothers and their 2 maternal uncles had Aarskog syndrome. An obligate heterozygote in this kindred was found to have partial expression of the disorder with hand and foot anomalies. Sugarman et al. (1973) favored sex-influenced autosomal dominant inheritance. Teebi et al. (1993) reported the case of an affected mother and 4 sons (including a pair of monozygotic twins) by 2 different husbands. They suggested that the manifestations were as severe in the mother as in the sons and that this suggested autosomal dominant inheritance. Actually, the mother seemed less severely affected, compatible with X-linked inheritance.
Escobar and Weaver (1978) reported a patient who had features more suggestive of the Noonan syndrome than of the Aarskog syndrome. The patient, aged 28 years, also had severe macrocytic anemia refractory to iron therapy, hepatomegaly, hemochromatosis, portal cirrhosis, and interstitial pulmonary disease.
Berry et al. (1980) suggested that the first report of this syndrome was that of Hanley et al. (1967), who described brothers with multiple osteochondritis dissecans (165800). The features were hypertelorism, cryptorchidism, digital contractures, sternal deformity, and osteochondritis dissecans at multiple sites. Early fusion of the manubrium and corpus sterni occurred. The ears were floppy; 'lop-ear' or cup-ear may be appropriately descriptive. One brother had ptosis.
Grier et al. (1981) observed typically affected father and son, a situation suggestive of autosomal dominant inheritance (with sex influence) for at least one form of the disorder; see 100050. The phenotype in both males was classic. The father was not related to the mother.
Van den Bergh et al. (1984) described a 17-year-old girl who developed the syndrome of benign intracranial hypertension after minor head trauma. A small area of congenital alopecia was found on the midline vertex and an underlying bony defect was revealed by skull x-rays. Cerebral angiography showed absence of the straight sinus and other abnormalities of cerebral venous drainage. A 9-year-old brother showed full-blown Aarskog syndrome. The proband, her sister, and her mother showed signs interpreted as features of Aarskog syndrome.
Friedman (1985) described the distinctive umbilical changes of Aarskog syndrome, Rieger syndrome (180500), and Robinow syndrome (180700). He quoted the famous monograph on the umbilicus by Cullen (1916), which had illustrations by Max Broedel. Two of 5 patients reported by Tsukahara and Fernandez (1994) had a protruding umbilicus and the other 3 had a characteristic umbilicus consisting of a smooth depression with radiating branches of the cicatrix and a flat cushion.
Nielsen (1988) reported the first Danish case of Aarskog syndrome in a child who had attended several specialized outpatient clinics before the diagnosis was suggested. In a review, Porteous and Goudie (1991) reported that they knew of at least 12 affected persons in a population of 1.6 million in the West of Scotland, but believed that the true incidence must be higher since the benign nature of the disorder results in underdiagnosis.
Mikelsaar and Lurie (1992) described a boy with features typical of Aarskog syndrome who also had leg lymphedema extending to the knees when examined at the age of 10 years. The lymphedema was presumably congenital but the age of onset was not stated. The mother had no features of the Aarskog syndrome, but the maternal grandfather showed hypertelorism, camptodactyly, and lymphedema of the feet. Fryns (1992) commented on the disappearance of manifestations in postpubertal males. Social integration and functioning as adults was usually satisfactory. Fryns (1993) described 2 unrelated males, aged 22 and 20, with episodes of chronic abdominal pain over several months. Investigations showed dolichomegarectosigmoid ('long and large rectum and sigmoid'); in both, sigmoid resection with end-to-end reanastomosis was performed after acute volvulus. For further information concerning the 22-year-old patient, see Casteels et al. (1994).
Fernandez et al. (1994) described 10 Japanese patients with Aarskog syndrome from 3 families. One of these patients had pulmonary stenosis, and another had ventricular septal defect. Analysis of the literature showed that congenital heart defects were described in 2 of 169 non-Japanese cases and in 2 of 20 previously reported Japanese cases. Fernandez et al. (1994) suggested that cardiac evaluation is indicated for all children with Aarskog syndrome.
Fryns (1992) concluded that the incidence of mental handicap in Aarskog syndrome may be as high as 30%. Logie and Porteous (1998) tested this observation in 21 males under 17 years of age with clinically confirmed Aarskog syndrome and found their IQs to lie within the normal range. They concluded that Aarskog syndrome is not associated with mental handicap. On the other hand, Lebel et al. (2002) found a missense mutation (300546.0005) in the FGD1 gene in 3 brothers with X-linked mental retardation. Although the brothers had short stature and small feet, they lacked distinct craniofacial, skeletal, or genital findings suggestive of Aarskog syndrome. Their mother was a carrier and was of normal intelligence.
Orrico et al. (2005) reported a 16-year-old boy who was evaluated for attention deficit-hyperactivity disorder (ADHD; 143465) and low intelligence quotient, in whom they noted dysmorphic features reminiscent of AAS. A missense mutation was found in the FGD1 gene (300546.0007). The authors stated that their findings supported the observation that a spectrum of behavioral disorders may be part of the AAS phenotype.
Bottani et al. (2007) reported a boy with classic Aarskog-Scott syndrome with normal neurologic status and good school performance. At age 9 years, he developed generalized seizures and was found to have unilateral focal frontoparietal polymicrogyria (see 610031), which had not previously been described in this syndrome. Genetic analysis identified a hemizygous mutation in the FGD1 gene (300546.0011).
Orrico et al. (2010) reported 11 patients with genetically confirmed Aarskog-Scott syndrome. Consistent features included hypertelorism, short nose, short broad hands, short stature, shawl scrotum, and genitourinary abnormalities. Secondary features, which were variable, included widow's peak, ptosis, downward slanting palpebral fissures, broad feet, abnormal auricles, umbilical hernia, and cryptorchidism. Five patients had developmental delay. Obesity was present in 4 (36.3%) patients.
Aarskog-Scott syndrome usually shows an X-linked recessive pattern of inheritance. Pilozzi-Edmonds et al. (2011) reported 2 fraternal twin brothers with the disorder, each of whom carried the same truncating mutation in the FGD1 gene. However, the mutation was not detected in the mother's lymphocytes, suggesting maternal germline mosaicism. The authors emphasized the implications for genetic counseling.
Tyrkus et al. (1980) described mother and son with Aarskog-Scott syndrome. Expression was complete in the mother. The mother and son had a reciprocal translocation between the X chromosome and chromosome 8. The breakpoint on the X was at Xq12. The mother's parents and sibs were clinically normal and the parents had normal karyotypes. Tyrkus et al. (1980) described parental exposure to ionizing radiation. They found that the Aarskog-Scott locus may be located at Xq12. The normal X chromosome in the mother was consistently inactivated. Thus the full expression in the mother was explained. Bawle et al. (1984) published definitively on the family in which a balanced X-autosome translocation was associated with Aarskog syndrome in mother and son. They placed the X chromosome breakpoint at Xq13. Noteworthy was the full expression in the mother comparable to the full expression of Duchenne muscular dystrophy (310200) in women with balanced X-autosome translocations involving Xp21. The authors postulated that, as in the latter case, the break at Xq13 creating the translocation also caused a presumed de novo point mutation in the 'Aarskog gene' and that the woman had nonrandom (preferential) inactivation of her structurally normal X. By high resolution cytogenetic studies, Rafael et al. (1992) demonstrated that the X chromosome breakpoint in the patient of Bawle et al. (1984) was located in the proximal short arm of the X chromosome rather than at Xq13. The autosomal breakpoint was 8q11 rather than 8p21.1, as previously reported. By study of somatic cell hybrids containing the der(X) chromosome by a combination of fluorescence in situ hybridization and Southern blot analysis with X-chromosome probes, Glover et al. (1993) refined the localization of the breakpoint to Xp11.21.
By SSCP analysis, Pasteris et al. (1994) identified a mutation (300546.0001) in the FGD1 gene in affected members of a family with Aarskog-Scott syndrome.
Orrico et al. (2000) analyzed 13 unrelated patients with the clinical diagnosis of Aarskog-Scott syndrome. One patient carried an arg610-to-gln mutation (300546.0002) located in 1 of the 2 pleckstrin homology (PH) domains of the FGD1 gene.
Using SSCP analysis of the FGD1 gene, Schwartz et al. (2000) identified a missense mutation (300546.0003) in a familial case of Aarskog-Scott syndrome and a deletion mutation (300546.0004) in a sporadic case.
Orrico et al. (2010) identified mutations in the FGD1 gene in 11 (18.33%) of 60 European patients with a clinically suspected diagnosis of Aarskog-Scott syndrome. Nine mutations were novel, including 3 missense mutations, 4 truncating mutations, an in-frame deletion, and a splice site mutation. One mutation (R656X; 300546.0012) was recurrent, present in 3 unrelated families. There were no apparent genotype/phenotype correlations.
Aarskog, D. A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J. Pediat. 77: 856-861, 1970. [PubMed: 5504078] [Full Text: https://doi.org/10.1016/s0022-3476(70)80247-5]
Baldellou, A., Galve, L., Bassecourt, M. Risk of medullary damage in Aarskog-Scott syndrome. (Abstract) Clin. Genet. 23: 225 only, 1983.
Bawle, E., Tyrkus, M., Lipman, S., Bozimowski, D. Aarskog syndrome: full male and female expression associated with an X-autosome translocation. Am. J. Med. Genet. 17: 595-602, 1984. [PubMed: 6711610] [Full Text: https://doi.org/10.1002/ajmg.1320170307]
Berman, P. A., Desjardins, C., Fraser, F. C. Inheritance of the Aarskog syndrome. Birth Defects Orig. Art. Ser. X(7): 151-159, 1974.
Berry, C., Cree, J., Mann, T. Aarskog's syndrome. Arch. Dis. Child. 55: 706-710, 1980. [PubMed: 7436535] [Full Text: https://doi.org/10.1136/adc.55.9.706]
Bottani, A., Orrico, A., Galli, L., Karam, O., Haenggeli, C.-A., Ferey, S., Conrad, B. Unilateral focal polymicrogyria in a patient with classical Aarskog-Scott syndrome due to a novel missense mutation in an evolutionary conserved RhoGEF domain of the faciogenital dysplasia gene FGD1. Am. J. Med. Genet. 143A: 2334-2338, 2007. [PubMed: 17847065] [Full Text: https://doi.org/10.1002/ajmg.a.31733]
Casteels, M., Samain, H., Penninckx, F., Coremans, G., Beirinckx, J., Fryns, J. P. Megadolichosigmoid in a young male with Aarskog syndrome. Genet. Counsel. 5: 81-83, 1994. [PubMed: 8031541]
Cullen, T. S. Embryology, Anatomy, and Diseases of the Umbilicus Together with Diseases of the Urachus. Philadelphia: W. B. Saunders (pub.) 1916.
Escobar, V., Weaver, D. D. Aarskog syndrome: new findings and genetic analysis. JAMA 240: 2638-2641, 1978. [PubMed: 712980] [Full Text: https://doi.org/10.1001/jama.240.24.2638]
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. [PubMed: 8209909] [Full Text: https://doi.org/10.1002/ajmg.1320500404]
Friedman, J. M. Umbilical dysmorphology: the importance of contemplating the belly button. Clin. Genet. 28: 343-347, 1985. [PubMed: 4064369] [Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb00408.x]
Fryns, J. P., Macken, J., Vinken, L., Igodt-Ameye, L., van den Berghe, H. The Aarskog syndrome. Hum. Genet. 42: 129-135, 1978. [PubMed: 669698] [Full Text: https://doi.org/10.1007/BF00283632]
Fryns, J. P. Aarskog syndrome: the changing phenotype with age. Am. J. Med. Genet. 43: 420-427, 1992. [PubMed: 1605221] [Full Text: https://doi.org/10.1002/ajmg.1320430164]
Fryns, J.-P. Dolichomegasigmoid in Aarskog syndrome. (Letter) Am. J. Med. Genet. 45: 122 only, 1993. [PubMed: 8418649] [Full Text: https://doi.org/10.1002/ajmg.1320450135]
Funderburk, S. J., Crandall, B. F. The Aarskog syndrome in three brothers. Clin. Genet. 6: 119-124, 1974. [PubMed: 4430151] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb00639.x]
Furukawa, C. T., Hall, B. D., Smith, D. W. The Aarskog syndrome. J. Pediat. 81: 1117-1122, 1972. [PubMed: 4643030] [Full Text: https://doi.org/10.1016/s0022-3476(72)80242-7]
Glover, T. W., Verga, V., Rafael, J., Barcroft, C., Gorski, J. L., Bawle, E. V., Higgins, J. V. Translocation breakpoint in Aarskog syndrome maps to Xp11.21 between ALAS2 and DXS323. Hum. Molec. Genet. 2: 1717-1718, 1993. [PubMed: 8268928] [Full Text: https://doi.org/10.1093/hmg/2.10.1717]
Grier, R. E., Farrington, F. H., Kendig, R., Mamunes, P. Autosomal dominant inheritance of the Aarskog phenotype. (Abstract) Am. J. Hum. Genet. 33: 64A only, 1981.
Hanley, W. B., McKusick, V. A., Barranco, F. T. Osteochondritis dissecans and associated malformations in brothers: a review of familial aspects. J. Bone Joint Surg. Am. 49: 925-937, 1967. [PubMed: 4382085]
Hoo, J. J. The Aarskog (facio-digito-genital) syndrome. Clin. Genet. 16: 269-276, 1979. [PubMed: 519896] [Full Text: https://doi.org/10.1111/j.1399-0004.1979.tb00999.x]
Kodama, M., Fujimoto, S., Namikawa, T., Matsuda, I. Aarskog syndrome with isolated growth hormone deficiency. Europ. J. Pediat. 135: 273-276, 1981. [PubMed: 7227381] [Full Text: https://doi.org/10.1007/BF00442102]
Lebel, R. R., May, M., Pouls, S., Lubs, H. A., Stevenson, R. E., Schwartz, C. E. Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene. Clin. Genet. 61: 139-145, 2002. [PubMed: 11940089] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.610209.x]
Logie, L. J., Porteous, M. E. M. Intelligence and development in Aarskog syndrome. Arch. Dis. Child. 79: 359-360, 1998. [PubMed: 9875050] [Full Text: https://doi.org/10.1136/adc.79.4.359]
Mikelsaar, R. V.-A., Lurie, I. W. Atypical case of Aarskog syndrome. J. Med. Genet. 29: 349-350, 1992. [PubMed: 1583665] [Full Text: https://doi.org/10.1136/jmg.29.5.349]
Nielsen, K. B. Aarskog syndrome in a Danish family: an illustration of the need for dysmorphology in paediatrics. Clin. Genet. 33: 315-317, 1988. [PubMed: 3359689] [Full Text: https://doi.org/10.1111/j.1399-0004.1988.tb03455.x]
Oberiter, V., Lovrencic, M. K., Schmutzer, L., Kraus, O. The Aarskog syndrome. Acta Paediat. Scand. 69: 567-570, 1980. [PubMed: 7446107] [Full Text: https://doi.org/10.1111/j.1651-2227.1980.tb07135.x]
Orrico, A., Galli, L., Buoni, S., Hayek, G., Luchetti, A., Lorenzini, S., Zappella, M., Pomponi, M. G., Sorrentino, V. 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. 135A: 99-102, 2005. [PubMed: 15809997] [Full Text: https://doi.org/10.1002/ajmg.a.30700]
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. Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene. Am. J. Med. Genet. 152A: 313-318, 2010. [PubMed: 20082460] [Full Text: https://doi.org/10.1002/ajmg.a.33199]
Orrico, A., Galli, L., Falciani, M., Bracci, M., Cavaliere, M. L., Rinaldi, M. M., Musacchio, A., Sorrentino, V. 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: 216-220, 2000. [PubMed: 10930571] [Full Text: https://doi.org/10.1016/s0014-5793(00)01857-3]
Pasteris, N. G., Cadle, A., Logie, L. J., Porteous, M. E. M., Schwartz, C. E., Stevenson, R. E., Glover, T. W., Wilroy, R. S., Gorski, J. L. Isolation and analysis of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative, rho/rac guanine nucleotide exchange factor. Cell 79: 669-678, 1994. [PubMed: 7954831] [Full Text: https://doi.org/10.1016/0092-8674(94)90552-5]
Pedersen, J. C., Fryns, J. P., Bracke, P., Geeraert, M., Van Den Berghe, H. The Aarskog syndrome. Ann. Genet. 23: 108-110, 1980. [PubMed: 6967282]
Pilozzi-Edmonds, L., Maher, T. A., Basran, R. K., Milunsky, A., Al-Thihli, K., Braverman, N. E., Alfares, A. Fraternal twins with Aarskog-Scott syndrome due to maternal germline mosaicism. Am. J. Med. Genet. 155A: 1987-1990, 2011. [PubMed: 21739585] [Full Text: https://doi.org/10.1002/ajmg.a.34094]
Porteous, M. E. M., Goudie, D. R. Aarskog syndrome. J. Med. Genet. 28: 44-47, 1991. [PubMed: 1999832] [Full Text: https://doi.org/10.1136/jmg.28.1.44]
Rafael, J., Verga, V., Hall, B., Burright, E., Gorski, J., Bawle, J., Higgins, J. V., Glover, T. W. Assignment of the translocation breakpoint in a patient with Aarskog syndrome to Xp11.21. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A116 only, 1992.
Schwartz, C. E., 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. [PubMed: 11093277] [Full Text: https://doi.org/10.1038/sj.ejhg.5200553]
Scott, C. I., Jr. Unusual facies, joint hypermobility, genital anomaly and short stature: a new dysmorphic syndrome. Birth Defects Orig. Art. Ser. VII(6): 240-246, 1971.
Sugarman, G. I., Rimoin, D. L., Lachman, R. S. The facial-digital-genital (Aarskog) syndrome. Am. J. Dis. Child. 126: 248-252, 1973. [PubMed: 4146757] [Full Text: https://doi.org/10.1001/archpedi.1973.02110190218022]
Teebi, A. S., Rucquoi, J. K., Meyn, M. S. Aarskog syndrome: report of a family with review and discussion of nosology. Am. J. Med. Genet. 46: 501-509, 1993. [PubMed: 8322809] [Full Text: https://doi.org/10.1002/ajmg.1320460508]
Tsukahara, M., Fernandez, G. I. Umbilical findings in Aarskog syndrome. Clin. Genet. 45: 260-265, 1994. [PubMed: 8076412] [Full Text: https://doi.org/10.1111/j.1399-0004.1994.tb04152.x]
Tyrkus, M., Bawle, E., Lipman, S., Bozimowski, D., Woolley, P. V., Jr. Aarskog-Scott syndrome inherited as an X-linked dominant with full male-female expression. (Abstract) Am. J. Hum. Genet. 32: 134A only, 1980.
van den Bergh, P., Fryns, J. P., Wilms, G., Piot, R., Dralands, G., van den Bergh, R. Anomalous cerebral venous drainage in Aarskog syndrome. Clin. Genet. 25: 288-294, 1984. [PubMed: 6705262] [Full Text: https://doi.org/10.1111/j.1399-0004.1984.tb01991.x]