GAPO Syndrome Clinical CharacteristicsOcular Features: Progressive optic atrophy is considered part of this syndrome but it is not a consistent feature. One patient with the suspected diagnosis had papilledema while other individuals may have congenital glaucoma, buphthalmos, band keratopathy, and keratoconus. White eyelashes have been described. Myelinated nerve retinal nerve fibers may be prominent. Systemic Features: This is a rare congenital disorder with so far incomplete phenotypic delineation. The diagnosis can be made soon after birth from the general facial and body morphology. The dysmorphism is secondary to marked bone growth retardation and metaphyseal dysplasia, resulting in a flat midface, frontal bossing, micrognathism, chest deformities, and vertebral anomalies. Psychomotor retardation is common but the extent of cognitive deficits is unknown. The permanent teeth may begin to develop but fail to erupt (pseudoanodontia). Even primary dentition is often abnormal. Alopecia is a feature although some individuals do have sparse body hair, at least for a period of time. Anomalous blood vessels such as dilated scalp veins are sometimes evident. Hypogonadism has been reported in both sexes. Individuals are subject to recurrent ear and respiratory infections. GeneticsGAPO occurs in both sexes. Homozygous mutations in the ANTXR1 gene (2p13.3) are responsible for this disorder. Pedigree: Autosomal recessiveTreatmentTreatment Options: Treatment is directed at individual problems. Prompt treatment of respiratory infections is important. ReferencesArticle Title: Mutations in ANTXR1 cause GAPO syndrome Stranecky V, Hoischen A, Hartmannova H, Zaki MS, Chaudhary A, Zudaire E, Noskova L, Baresova V, Pristoupilova A, Hodanova K, Sovova J, Hulkova H, Piherova L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martasek P, Baxova A, Afifi HH, St Croix B, Brunner HG, Temtamy S, Kmoch S. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9. PubMed ID: 23602711 GAPO syndrome: four new patients with congenital glaucoma and myelinated retinal nerve fiber layer Bozkurt B, Yildirim MS, Okka M, Bitirgen G. GAPO syndrome: four new patients with congenital glaucoma and myelinated retinal nerve fiber layer. Am J Med Genet A. 2013 Apr;161(4):829-34. PubMed ID: 23494824 GAPO syndrome: a new case of this rare syndrome and a review of the relative importance of different phenotypic features in diagnosis Bacon W, Hall RK, Roset JP, Boukari A, Tenenbaum H, Walter B. GAPO syndrome: a new case of this rare syndrome and a review of the relative importance of different phenotypic features in diagnosis. J Craniofac Genet Dev Biol. 1999 Oct-Dec;19(4):189-200. Review. PubMed ID: 10731088 Ophthalmic findings in GAPO syndrome Ilker SS, Ozturk F, Kurt E, Temel M, Gul D, Sayli BS. Ophthalmic findings in GAPO syndrome. Jpn J Ophthalmol. 1999 Jan-Feb;43(1):48-52. PubMed ID: 10197743 Read more about GAPO Syndrome
Mutations in ANTXR1 cause GAPO syndrome Stranecky V, Hoischen A, Hartmannova H, Zaki MS, Chaudhary A, Zudaire E, Noskova L, Baresova V, Pristoupilova A, Hodanova K, Sovova J, Hulkova H, Piherova L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martasek P, Baxova A, Afifi HH, St Croix B, Brunner HG, Temtamy S, Kmoch S. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9. PubMed ID: 23602711
GAPO syndrome: four new patients with congenital glaucoma and myelinated retinal nerve fiber layer Bozkurt B, Yildirim MS, Okka M, Bitirgen G. GAPO syndrome: four new patients with congenital glaucoma and myelinated retinal nerve fiber layer. Am J Med Genet A. 2013 Apr;161(4):829-34. PubMed ID: 23494824
GAPO syndrome: a new case of this rare syndrome and a review of the relative importance of different phenotypic features in diagnosis Bacon W, Hall RK, Roset JP, Boukari A, Tenenbaum H, Walter B. GAPO syndrome: a new case of this rare syndrome and a review of the relative importance of different phenotypic features in diagnosis. J Craniofac Genet Dev Biol. 1999 Oct-Dec;19(4):189-200. Review. PubMed ID: 10731088
Ophthalmic findings in GAPO syndrome Ilker SS, Ozturk F, Kurt E, Temel M, Gul D, Sayli BS. Ophthalmic findings in GAPO syndrome. Jpn J Ophthalmol. 1999 Jan-Feb;43(1):48-52. PubMed ID: 10197743
Waardenburg Syndrome, Type 3 Clinical CharacteristicsOcular Features: Type 3 Waardenburg syndrome has many of the features of other types but with the addition of upper limb anomalies. Dystopia canthorum and a broad nasal root are characteristic. Iris heterochromia is present in some patients. Hypopigmentation may be seen in lashes and eyebrows. Systemic Features: The upper limbs may appear underdeveloped with flexion contractures, fusion of the carpal bones and sometimes syndactyly. A white forelock may or may not be present. The cranial bones may be anomalous and rare patients can have microcephaly with significant mental retardation. Mental function is usually normal though. Occasional patients have cleft palate and/or lip. Hearing loss is of the sensorineural type. Hypopigmented skin patches are sometimes present but not all patients have them. GeneticsThe uniqueness of Waardenburg syndrome types 1 and 3 remains to be established. Mutations in the PAX3 gene are responsible for both types and both have been found in the same family. The phenotype is transmitted in an autosomal dominant pattern in either case but several families have been reported with type 1 WS in parents heterozygous for PAX3 mutations who had a homozygous child with the type 3 phenotype. However, heterozygous individuals with type 3 have also been reported and the relationship of the two types remains unknown. Craniofacial-deafness-hand syndrome(122880) with mutations in PAX3 has many features similar to those found in Waardenburg syndrome type 3 and may or may not be a unique disorder. Pedigree: Autosomal dominantAutosomal recessiveTreatmentTreatment Options: There is no treatment for the syndrome but cochlear implants might be helpful. ReferencesArticle Title: Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome Wollnik B, Tukel T, Uyguner O, Ghanbari A, Kayserili H, Emiroglu M, Yuksel-Apak M. Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. Am J Med Genet A. 2003 Sep 15;122A(1):42-5. PubMed ID: 12949970 Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I) Hoth CF, Milunsky A, Lipsky N, Sheffer R, Clarren SK, Baldwin CT. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). Am J Hum Genet. 1993 Mar;52(3):455-62. PubMed ID: 8447316 Upper limb involvement in the Klein-Waardenburg syndrome Goodman RM, Lewithal I, Solomon A, Klein D. Upper limb involvement in the Klein-Waardenburg syndrome. Am J Med Genet. 1982 Apr;11(4):425-33. PubMed ID: 7091186 Read more about Waardenburg Syndrome, Type 3
Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome Wollnik B, Tukel T, Uyguner O, Ghanbari A, Kayserili H, Emiroglu M, Yuksel-Apak M. Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. Am J Med Genet A. 2003 Sep 15;122A(1):42-5. PubMed ID: 12949970
Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I) Hoth CF, Milunsky A, Lipsky N, Sheffer R, Clarren SK, Baldwin CT. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). Am J Hum Genet. 1993 Mar;52(3):455-62. PubMed ID: 8447316
Upper limb involvement in the Klein-Waardenburg syndrome Goodman RM, Lewithal I, Solomon A, Klein D. Upper limb involvement in the Klein-Waardenburg syndrome. Am J Med Genet. 1982 Apr;11(4):425-33. PubMed ID: 7091186
Waardenburg Syndrome, Type 4 Clinical CharacteristicsOcular Features: The skin and ocular pigmentary changes and the sensorineural hearing loss in type 4 Waardenburg syndrome resembles that of other types. Patients, however, usually lack synophrys and dystopia canthorum. Systemic Features: Type 4 Waardenburg syndrome is largely similar to other types except that many patients also have Hirschsprung disease. GeneticsBoth autosomal dominant and recessive inheritance have been reported for type 4 Waardenburg syndrome. Both heterozygous and homozygous mutations in the EDNRB (endothelin-B receptor) gene (13q22) occur in patients. The aganglionic megacolon feature may be dose sensitive since homozygotes have been reported to have a 74% chance of developing Hirschsprung disease while only 21% of heterozygotes do so. Types 4A (277580) and 4B (613265) are both caused by mutations in the EDNRB gene, and type 4C (613266) results from a mutation in the SOX10 gene. Waardenburg syndrome WS2E is allelic to type 4C. This is an example of genetic heterogeneity both within the main types and within the subtypes. Pedigree: Autosomal dominantAutosomal recessiveTreatmentTreatment Options: No ocular treatment is necessary but assistive hearing devices can be beneficial. ReferencesArticle Title: Review and update of mutations causing Waardenburg syndrome Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010 Apr;31(4):391-406. Review. PubMed ID: 20127975 Waardenburg syndrome Read AP, Newton VE. Waardenburg syndrome. J Med Genet. 1997 Aug;34(8):656-65. Review. PubMed ID: 9279758 Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease Atti?(c) T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, Munnich A, Lyonnet S. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet. 1995 Dec;4(12):2407-9. PubMed ID: 8634719 Read more about Waardenburg Syndrome, Type 4
Review and update of mutations causing Waardenburg syndrome Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010 Apr;31(4):391-406. Review. PubMed ID: 20127975
Waardenburg syndrome Read AP, Newton VE. Waardenburg syndrome. J Med Genet. 1997 Aug;34(8):656-65. Review. PubMed ID: 9279758
Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease Atti?(c) T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, Munnich A, Lyonnet S. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet. 1995 Dec;4(12):2407-9. PubMed ID: 8634719
