title: Homozygous microdeletion of the POU1F1, CHMP2B, and VGLL3 genes in chromosome 3--a novel syndrome.
abstract: Microdeletion syndromes include numerous syndromic phenotypes associated with intellectual disability and dysmorphic features. We report on a patient with a novel microdeletion of chromosomal region 3p11.2-p12.1 containing POU1F1, chromatin-modifying protein 2B (CHMP2B), and vestigial-like 3 (VGLL3) genes. Our patient was diagnosed as having a neonatal multiple pituitary hormone [growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin] deficiency. In addition to the typical findings associated with these hormonal deficiencies, she exhibited clinical features resembling those of Laron syndrome (frontal bossing, saddle nose, small chin, blue sclera, and acromicria), with moderate intellectual disability. She also displayed an unusual growth pattern characterized by unresponsiveness to high doses of GH replacement therapy during infancy and early childhood and an accelerated growth rate beginning at the age of 4.5 years. Insulin-like growth factor (IGF)-1 levels were consistently extremely low or undetectable. Extensive medical and genetic analysis ruled out primary and secondary GH insensitivity. The distinct phenotype and the peculiar growth pattern observed in this affected patient, not reported to have been observed in other cases with POU1F1 gene inactivity, suggest that the other two deleted genes play a possible role in the development of this syndrome. This hypothesis may be supported by the fact that both the CHMP2B and VGLL3 genes are expressed in the liver and the growth plate, the two main target organs of the GH/IGF-1 axis. The homozygous deletion of the CHMP2B gene, previously associated with frontotemporal dementia, may contribute to the intellectual disability observed in this patient.
authors.affiliation: The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel. galiagy@post.tau.ac.il
authors.forename: Galia
authors.initials: G
authors.lastname: Gat-Yablonski
authors.forename: Rachel
authors.initials: R
authors.lastname: Frumkin-Ben David
authors.forename: Meytal
authors.initials: M
authors.lastname: Bar
authors.forename: Olga
authors.initials: O
authors.lastname: Potievsky
authors.forename: Moshe
authors.initials: M
authors.lastname: Phillip
authors.forename: Liora
authors.initials: L
authors.lastname: Lazar
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D002648:Child; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D005260:Female; D013006:Growth Hormone / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008607:Intellectual Disability / Q000235:genetics; D007557:Israel; D046150:Laron Syndrome; D008099:Liver / Q000378:metabolism; D047928:Premature Birth; D011388:Prolactin / Q000172:deficiency / Q000235:genetics; D013972:Thyrotropin / Q000172:deficiency / Q000235:genetics; D050817:Transcription Factor Pit-1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; C494187:POU1F1 protein, human; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C555441:VGLL3 protein, human; D007334:Insulin-Like Growth Factor I; D011388:Prolactin; D013972:Thyrotropin; D013006:Growth Hormone