Intellectual Developmental Disorder With Dysmorphic Facies, Seizures, And Distal Limb Anomalies

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is caused by homozygous mutation in the OTUD6B gene (612021) on chromosome 8q21.

Description

IDDFSDA is an autosomal recessive severe multisystem disorder characterized by poor overall growth, developmental delay, early-onset seizures, intellectual disability, and dysmorphic features. There is phenotypic variability. The most severely affected patients have a neurodevelopmental disorder with microcephaly, absent speech, and inability to walk, and they require feeding tubes. Some patients have congenital heart defects or nonspecific abnormalities on brain imaging. Less severely affected individuals have mild to moderate intellectual disability with normal speech and motor development (summary by Santiago-Sim et al., 2017).

Clinical Features

Santiago-Sim et al. (2017) reported 9 patients from 5 unrelated families with a neurodevelopmental disorder characterized by significant global developmental delay apparent since infancy and absent speech even in the teenaged patients. All patients had early-onset seizures; most seizures were generalized tonic-clonic, but some were absence, myoclonic, and atonic. The severity and the frequency of seizures was highly variable, with 1 patient having only a single seizure at age 4. The patients had hypotonia and poor motor development; all but 1 were nonambulatory. Most patients had intrauterine growth retardation, and all had severe feeding difficulties, often associated with failure to thrive and poor overall growth; 3 patients required a feeding tube. Two sibs had spastic quadriplegia, and 3 sibs from another family had autism spectrum disorder. Brain imaging was normal in 3 patients, but showed nonspecific changes in 6 patients, including cortical changes, white matter atrophy, enlarged ventricles, and hypoplastic corpus callosum. All patients had variable dysmorphic features, including microcephaly (up to -6.5 SD), brachycephaly, flat occiput, arched eyebrows, long downslanting palpebral fissures, long nose, broad nasal root, smooth long philtrum, thin upper lip, retrognathia, high-arched palate, large protruding low-set ears, and short neck. Other congenital malformations included cardiac septal defects (4 patients), sacral dimple (2 patients), cryptorchidism (3 patients), scoliosis, and abnormalities of the distal extremities, such as broad thumbs, hyperextensibility of the interphalangeal joints, clubfeet, and overlapping toes. Two of the patients had deceased sibs with a similar disorder.

Clinical Variability

Santiago-Sim et al. (2017) reported 3 sibs, born of consanguineous Turkish parents, with a slightly less severe form of IDDFSDA. They presented with seizures at 18 months, 7 years, and 8 years of age. The patients, who ranged in age from 14 to 20 years, had mild to moderate intellectual disability and no speech or motor delay. They had dysmorphic features, including wide forehead, narrow long face, and high-arched palate; 1 patient had downslanting palpebral fissures, tubular nose, and prominent dysplastic ears. Other features included arachnodactyly and hyperextensibility of the elbows. Brain imaging was normal.

Inheritance

The transmission pattern of IDDFSDA in the families reported by Santiago-Sim et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 12 patients from 6 unrelated families with IDDFSDA, Santiago-Sim et al. (2017) identified 4 homozygous mutations in the OTUD6B gene (612021.0001-612021.0004). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patients from 5 families had a truncating mutation associated with a more severe phenotype; patients in the sixth family had a missense mutation and a slightly less severe phenotype. The findings were consistent with a loss-of-function effect. Peripheral blood cells from 1 patient with a truncating mutation (612021.0002) showed decreased chymotrypsin-like activity of the 26S proteasome complex and substantially reduced incorporation of 19S subunits into 26S proteasomes. This was associated with accumulation of ubiquitin-protein conjugates. Transmission electron microscopy showed abnormal cytoplasmic inclusions in lymphocytes, suggesting that these inclusions represent accumulation of protein substrates due to an imbalance in ubiquitination/deubiquitination activities. The findings indicated that dysregulation of the ubiquitin system is the cause of this multisystem disease.

Animal Model

Santiago-Sim et al. (2017) reported that homozygous Otud6b-null mice die between embryonic day 18.5 and shortly after birth. Mutant embryonic mice showed intrauterine growth retardation and a high percentage of ventricular septal cardiac defects.