title: Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.
abstract: Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.
authors.affiliation: Department of Human Genetics, 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: Barto J
authors.initials: BJ
authors.lastname: Otten
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schoots
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Salim
authors.initials: S
authors.lastname: Aftimos
authors.forename: Jumana Y
authors.initials: JY
authors.lastname: Al-Aama
authors.forename: Yolande
authors.initials: Y
authors.lastname: van Bever
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bober
authors.forename: George F
authors.initials: GF
authors.lastname: Borm
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: Cheri L
authors.initials: CL
authors.lastname: Deal
authors.forename: Alaa Y
authors.initials: AY
authors.lastname: Edrees
authors.forename: Murray
authors.initials: M
authors.lastname: Feingold
authors.forename: Alan
authors.initials: A
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
authors.initials: D
authors.lastname: Johnson
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
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: A Erik
authors.initials: AE
authors.lastname: Sluiter
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: D018797:Cell Cycle Proteins / Q000235:genetics; D002675:Child, Preschool; D015331:Cohort Studies; D065817:Congenital Microtia; D004423:Ear / Q000002:abnormalities; D005260:Female; D057238:Growth Charts; D006130:Growth Disorders / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D019382:Human Growth Hormone / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D008297:Male; D008844:Micrognathism / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D009154:Mutation; D051738:Origin Recognition Complex / Q000235:genetics; D010329:Patella / Q000002:abnormalities; D046468:Sexual Development / Q000235:genetics; D014564:Urogenital Abnormalities
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D051738:Origin Recognition Complex; D019382:Human Growth Hormone