Clinical Description
DDX11-related cohesinopathy is characterized by a clinical triad of severe microcephaly, growth restriction, and hearing loss. Other anomalies have also been described. To date, 26 individuals have been identified with biallelic pathogenic variants in DDX11 [van der Lelij et al 2010, Capo-Chichi et al 2013, Bailey et al 2015, Eppley et al 2017, Alkhunaizi et al 2018, Bottega et al 2019, Cortone et al 2018, Rabin et al 2019, van Schie et al 2020, Arroyo-Carrera et al 2023, Kratochwila et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.
Microcephaly has a prenatal onset and is reported in all affected individuals. Congenital microcephaly can range from 3.3 to 10 standard deviations (SD) below the mean for age and sex. Postnatal head growth velocity is slower than average for age and sex. However, there are no reports of a substantial decrease in head growth velocity in childhood.
Prenatal and postnatal growth deficiency. All 26 reported individuals to date had intrauterine growth deficiency with birth weight and height below the third centile. Postnatal growth deficiency was also reported in all individuals; two individuals had weights between the 50th and 75th percentile later in childhood, after they were started on gastrostomy tube feedings [Bailey et al 2015, Alkhunaizi et al 2018].
Congenital sensorineural hearing loss is usually severe and is due to bilateral hypoplasia of the cochlea and the cochlear nerve. Children with DDX11-related cohesinopathy usually present early with a failed newborn hearing screen or severe speech disability that is comparable to the degree of sensorineural hearing loss. Expressive language is consistently affected due to the hearing loss; receptive language is also involved but to a lesser degree. Sign language can be learned; however, due to the intellectual disability, this is also limited in some individuals along with receptive language.
Intellectual disability and developmental delay range from mild to moderate and tend to be stable. Gross and fine motor milestones are usually attained at the usual time although a few individuals have mild delays.
Behavioral issues such as mild attention-deficit/hyperactivity disorder (ADHD) and/or aggression were reported in a couple of individuals [Bailey et al 2015, Alkhunaizi et al 2018, van Schie et al 2020]; however, affected children usually have good interpersonal skills.
Skeletal anomalies are commonly seen (16/23 individuals), including proximal insertion of thumbs, shortened first metacarpals, small radii, syndactyly, and short thumbs.
Additional structural brain abnormalities. In addition to cochlear hypoplasia, one individual presented with posterior labyrinthine anomaly with persistent lateral semicircular canal anlage [Alkhunaizi et al 2018]. Eight individuals presented with brain anomalies including focal poor sulcation pattern, delayed gyration, focal lissencephaly, corpus callosum hypoplasia, and cerebellar vermis hypoplasia [Alkhunaizi et al 2018, Rabin et al 2019, van Schie et al 2020, Kratochwila et al 2024].
Cardiovascular anomalies are reported in 33% (7/21 individuals). These include patent ductus arteriosus (1), small atrial septal defect with large patent ductus arteriosus (1), ventricular septal defect (4), and tetralogy of Fallot (1).
Other manifestations reported in single individuals (or sibs):
Limb anomalies including fifth finger clinodactyly, brachydactyly, small fibula, talipes equinovarus, and overlapping toes
Abnormal skin pigmentation including café au lait macules, cutis marmorata, hypo- or hyperpigmentation, and livedo reticularis with telangiectasia
Genitourinary malformations including hypoplastic scrotum, cryptorchidism, hypospadias, and multicystic kidneys
Malignancy.
DDX11 is essential for genome maintenance and may act as a tumor suppressor [Parish et al 2006]. The possibility of an increased risk of malignancy in obligate heterozygotes (parents) was raised by van der Lelij et al [2010], who reported a family that included a mother of the proband with lymphoma and another heterozygous relative with endometrial adenocarcinoma. None of the five affected individuals nor their parents reported by Alkhunaizi et al [2018] had cancer. Moreover, the oldest individual known to date with DDX11-related cohesinopathy died at age 64 years with no evidence of cancer [van Schie et al 2020]. Therefore, the risk of malignancy in individuals with DDX11-related cohesinopathy or heterozygous individuals remains unproven.