Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients.
Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.
Département de Génétique, Hôpital Necker-Enfants Malades, APHP, Paris, France.
Daphné
D
Lehalle
Christopher T
CT
Gordon
Myriam
M
Oufadem
Géraldine
G
Goudefroye
Lucile
L
Boutaud
Jean-Luc
JL
Alessandri
Neus
N
Baena
Geneviève
G
Baujat
Clarisse
C
Baumann
Odile
O
Boute-Benejean
Roseline
R
Caumes
Charles
C
Decaestecker
Dominique
D
Gaillard
Alice
A
Goldenberg
Marie
M
Gonzales
Muriel
M
Holder-Espinasse
Marie-Line
ML
Jacquemont
Didier
D
Lacombe
Sylvie
S
Manouvrier-Hanu
Sandrine
S
Marlin
Michèle
M
Mathieu-Dramard
Gilles
G
Morin
Laurent
L
Pasquier
Florence
F
Petit
Marlène
M
Rio
Robert
R
Smigiel
Christel
C
Thauvin-Robinet
Alexandre
A
Vasiljevic
Alain
A
Verloes
Valérie
V
Malan
Arnold
A
Munnich
Loïc
L
de Pontual
Michel
M
Vekemans
Stanislas
S
Lyonnet
Tania
T
Attié-Bitach
Jeanne
J
Amiel
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology*; D001006:Anus, Imperforate / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D004431:Ear, External / Q000473:pathology; D005260:Female; D006228:Hand Deformities, Congenital / Q000235:genetics / Q000473:pathology*; D057895:Haploinsufficiency; D006312:Hearing Loss, Bilateral / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology*; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000235:genetics / Q000473:pathology*; D008831:Microcephaly / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009886:Ophthalmoplegia / Q000235:genetics / Q000473:pathology*; D010445:Peptide Elongation Factors / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011247:Pregnancy; D011296:Prenatal Diagnosis; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics* / Q000378:metabolism*; D013921:Thrombocytopenia / Q000235:genetics / Q000473:pathology*
C581608:EFTUD2 protein, human; D010445:Peptide Elongation Factors; D017415:Ribonucleoprotein, U5 Small Nuclear
EFTUD2; mandibulofacial dysostosis; microcephaly; spliceosome