Expanding the Phenotype of the FAM149B1-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family

Biallelic truncating FAM149B1 variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known FAM149B1 c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in FAM149B1-ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the FAM149B1-related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of FAM149B1-related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.

Biallelic CDK9 variants as a cause of a new multiple-malformation syndrome with retinal dystrophy mimicking the CHARGE syndrome

CDK9 has been considered a candidate gene involved in the CHARGE-like syndrome in a pair of cousins. We report an 8-year-old boy with a strikingly similar phenotype including facial asymmetry, microtia with preauricular tags and bilateral hearing loss, cleft lip and palate, cardiac dysrhythmia, and undescended testes. Joint contracture, no finger flexion creases, and large halluces were the same as those of a previously reported patient with homozygous CDK9 variants. The ocular phenotype included blepharophimosis, lacrimal duct obstruction, eyelid dermoids, Duane syndrome-like abduction deficit, and congenital cataracts. Optical coherence tomography and electroretinography evaluations revealed severe retinal dystrophy had developed at an early age. Trio-based whole-exome sequencing identified compound heterozygous variants in CDK9 [p.(A288T) of maternal origin and p.(R303C) of paternal origin] in the patient. Variants’ kinase activities were reduced compared with wild type. We concluded that CDK9 biallelic variants cause a CHARGE-like malformation syndrome with retinal dystrophy as a distinguishing feature.

Outcomes of symmetric bilateral medial rectus recession in large-angle esotropic Duane syndrome

Purpose: To evaluate the efficacy of symmetric bilateral medial rectus recession in large-angle esotropic Duane retraction syndrome (DRS) with moderate to severe globe retraction. Methods: In a retrospective study, medical reports of 30 patients with esotropia of equal or more than 20 prism diopters (pd) and moderate to serve globe retraction due to unilateral DRS who underwent symmetric bilateral medial rectus recession were reviewed. Age, gender, laterality, amblyopia, length of follow-up, pre- and postoperative measurements of primary position deviation, ocular ductions and severity of globe retraction and abnormal head posture were evaluated. A successful result was defined as decreasing esotropia to equal or less than 8 pd or equal or less than 8 pd of consecutive exotropia. Results: The mean age of patients at surgery was 13.7 ± 8.5 years old (range: 3–38). The mean preoperative esotropia measured 28.9 ± 9.1 pd in distance and 25.7 ± 7.2 pd in near, which decreased to 4.9 ± 6.1 pd in distance and 3.9 ± 8.8 pd in near postoperatively. The mean bilateral medial rectus recession was 4.9 ± 0.9 mm (range: 3–6 mm). The mean abnormal head posture improved from 19.1 ± 6.9 degrees (range: 10–30 degrees) to 3.3 ± 4.7 degrees (range: 0-15 degrees) postoperatively. At the last follow-up visit, 23 patients (76.7%) had a successful outcome. Conclusions: In the large-angle esotropic DRS patients with moderate to severe globe retraction, symmetric bilateral medial rectus recession, can be conducted to successfully resolve primary position deviation and abnormal head posture.

Unilateral Duane Retraction Syndrome Associated with Unilateral Congenital Cataract

Purpose: To report unilateral congenital cataract in a case of ipsilateral Duane retraction syndrome. Case Report: In this case, we present a six year old girl who was referred with ocular deviation. She had a history of congenital cataract surgery in the left eye at the age of two years. The subject had no associated systemic disease, developmental delay, or positive family history. She was finally diagnosed as having Duane retraction syndrome in the same eye. Conclusion: Duane retraction syndrome can be associated with congenital cataract due to the matching time of gestational development of the lens to that of ocular and nonocular anomalies associated with Duane syndrome. As both of these disorders are rare, coincidence of both in the same person and the same eye by chance is a very remote possibility.