title: Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.
abstract: Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.
authors.affiliation: Department of Human Genetics 836, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sonja A
authors.initials: SA
authors.lastname: de Munnik
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Salim
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authors.lastname: Aftimos
authors.forename: Jumana Y
authors.initials: JY
authors.lastname: Al-Aama
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authors.lastname: van Bever
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authors.lastname: Edrees
authors.forename: Murray
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authors.lastname: Fryer
authors.forename: Johanna M
authors.initials: JM
authors.lastname: van Hagen
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Maaike C E
authors.initials: MC
authors.lastname: Jansweijer
authors.forename: Diana
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authors.lastname: Johnson
authors.forename: Sarina G
authors.initials: SG
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authors.forename: John M
authors.initials: JM
authors.lastname: Opitz
authors.forename: A Radha
authors.initials: AR
authors.lastname: Ramadevi
authors.forename: Willie
authors.initials: W
authors.lastname: Reardon
authors.forename: Alison
authors.initials: A
authors.lastname: Ross
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.forename: Constance T R M
authors.initials: CT
authors.lastname: Schrander-Stumpel
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schoots
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.forename: Paulien A
authors.initials: PA
authors.lastname: Terhal
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.forename: David L
authors.initials: DL
authors.lastname: Skidmore
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D065817:Congenital Microtia; D004423:Ear / Q000002:abnormalities; D005260:Female; D056726:Genetic Association Studies; D006130:Growth Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008844:Micrognathism / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D051738:Origin Recognition Complex / Q000235:genetics*; D010329:Patella / Q000002:abnormalities / Q000378:metabolism
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D051738:Origin Recognition Complex