Short Stature, Hearing Loss, Retinitis Pigmentosa, And Distinctive Facies

A number sign (#) is used with this entry because of evidence that short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF) is caused by homozygous or compound heterozygous mutation in the EXOSC2 gene (602238) on chromosome 9q34.

Description

SHRF is an autosomal recessive disorder characterized by short stature, brachydactyly, dysmorphic facial features, hearing loss, and visual impairment. Onset of the hearing and visual abnormalities, including retinitis pigmentosa, varies from birth to the second decade. Patients have mild intellectual disability and mild cerebellar atrophy with myelination defects on brain imaging (summary by Di Donato et al., 2016).

Clinical Features

Di Donato et al. (2016) reported 3 patients from 2 unrelated German families with a similar complex congenital phenotype. In family 1, a 6-year-old girl (patient 1) and her 44-year-old paternal aunt (patient 2) were affected. They both had delayed development with mild intellectual disability, short stature (-2.4 and -3.3 SD, respectively), brachydactyly, broad terminal phalanges, particularly thumbs, and common dysmorphic facial features, including sparse hair, high forehead, deep-set eyes, short upslanting palpebral fissures, short nose, anteverted nares, wide nasal base with broad nasal tip and broad columella, long philtrum, thin upper lip, and low-set, posteriorly rotated ears. Both had sensorineural hearing loss and myopia, apparent from birth in the niece and in the first decade in the aunt. The aunt also developed retinitis pigmentosa, corneal dystrophy, glaucoma, and hypothyroidism. Patient 3 was a 28-year-old man from an unrelated family who presented in the first years of life with short stature, congenital hypothyroidism, and delayed psychomotor development with speech delay. He also showed myopia, nystagmus, facial anomalies similar to those in the first family, and brachydactyly with broad thumbs. In the first and second decades of life, he developed progressive hearing loss, retinitis pigmentosa, and diabetes mellitus. Height was -4.8 SD at age 28. Patients 2 and 3 had the appearance of premature aging with sparse hair and arterial hypertension. Brain imaging in all 3 patients showed cerebellar atrophy; the 2 youngest patients had delayed myelination/dysmyelination. Patient 3 had calcifications in basal ganglia and thalamus. All patients were able to attend special schools.

Inheritance

The transmission pattern of SHRF in the families reported by Di Donato et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated German families with SHRF, Di Donato et al. (2016) identified homozygous or compound heterozygous mutations in the EXOSC2 gene (G30V, 602238.0001 and G198D, 602238.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in both families. The G30V variant was found in all 3 patients and at a low frequency in German controls, suggesting a common founder allele in this population. Functional studies of the variants and studies of patient cells were not performed, but structural modeling suggested that the variants were deleterious.