Cataracts, Growth Hormone Deficiency, Sensory Neuropathy, Sensorineural Hearing Loss, And Skeletal Dysplasia

A number sign (#) is used with this entry because of evidence that CAGSSS, which comprises cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, is caused by homozygous or compound heterozygous mutation in the IARS2 gene (612801) on chromosome 1q41.

Description

CAGSSS, which comprises cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, is an autosomal recessive multisystemic disorder with a highly variable phenotypic spectrum. Not all of these features are always present, and almost all the features may present at different times and/or become more apparent with age. The skeletal features are consistent with spondyloepimetaphyseal dysplasia (SEMD) (summary by Vona et al., 2018).

One family had a distinctive presentation with infantile-onset intractable seizures and cortical abnormalities reminiscent of Leigh syndrome (see 256000). The correlation between genotype and phenotype remains unclear, but since the IARS2 gene is involved in mitochondrial function, heterogeneous manifestations can be expected (Takezawa et al., 2018).

Clinical Features

Liberfarb et al. (1993) reported 2 patients from a large French Canadian family with a form of autosomal recessive congenital hereditary sensory and motor neuropathy with additional features. The patients presented in infancy with congenital cataracts, nystagmus, delayed motor development, and mild dysmorphic features, including depressed nasal bridge and long philtrum. Both had distal sensory impairment and hyporeflexia; electrophysiologic studies confirmed a peripheral neuropathy. Sural nerve biopsy in 1 patient showed a marked decrease in small and medium myelinated fibers. Both patients also had short stature due to growth hormone deficiency and some bone abnormalities, such as scoliosis: one had congenital hip dysplasia and the other had joint contractures. One patient had sensorineural hearing loss. Cognition was normal. Schwartzentruber et al. (2014) reported another affected member of the family reported by Liberfarb et al. (1993). She had congenital hip dislocation, spinal stenosis, and multiple skeletal anomalies consistent with a diagnosis of spondyloepiphyseal dysplasia. There was delayed motor development and short stature due to growth hormone deficiency; brain MRI showed atrophy of the pituitary, and she may have had central cortisol deficiency. Other features included distal sensory neuropathy, hearing loss, and cataracts. She was also noted to have type II esophageal achalasia. Cognition was normal.

Moosa et al. (2017) reported an 8-year-old girl, born of unrelated Danish parents, with evolving features of CAGSSS. She presented at birth with hip dislocation and craniofacial abnormalities, including high prominent forehead, flat nasal bridge, infraorbital creases, small nose with hypoplastic nares, deep nasolabial folds, thin lips, micrognathia, midface hypoplasia, and dysplastic ears. She had delayed motor milestones, hypotonia, hyperextensible joints, short thorax, brachydactyly, tapering fingers, pes planus, and skin telangiectasia with sun sensitivity. She had short stature (-6 SD), but not growth hormone deficiency. Ophthalmologic examination showed nystagmus and hyperopia, and she developed cataracts at age 3. She also had insensitivity to pain and recurrent slow-healing wounds, consistent with peripheral neuropathy, and was diagnosed with sensorineural hearing loss at age 8 years. Cognition was normal. Skeletal and radiographic abnormalities included hyperlordosis, genu valgus, shortened long bones, hip subluxation, irregular and flared metaphyses, delayed ossification of the epiphyses, absent capital femoral epiphyses, and abnormal vertebral bodies with remnants of coronal clefts. The skeletal features became more severe with age. Moosa et al. (2017) concluded that the skeletal phenotype was consistent with spondyloepimetaphyseal dysplasia (SEMD). Family history revealed 3 pregnancy losses, the cause of which was unknown.

Vona et al. (2018) reported 3 patients from 2 unrelated consanguineous Iranian families with variable manifestations of CAGSSS. The patients were adults at the time of the report; all had normal intelligence. In the first family, the only affected individual was a 20-year-old man who presented in infancy with congenital cataracts, nystagmus, strabismus, myopia, mild spasticity, and mildly delayed motor development. He later developed short stature (-3.4 SD) associated with growth hormone deficiency and showed radiographic evidence of spondyloepimetaphyseal dysplasia with associated skeletal abnormalities, including scoliosis, pes planus, tapering fingers, and shortened femoral neck. Sensorineural hearing loss and sensorimotor axonal polyneuropathy were diagnosed at age 13 and 16 years, respectively. He was also found to have type II esophageal achalasia in infancy and later onset of central adrenal insufficiency. Craniofacial features included prognathism, midface retrusion, short philtrum, thin upper lip, thick eyebrows, and long neck. Two sisters from the second family had congenital cataracts and skeletal abnormalities, including short stature, femoral head deformities, metaphyseal widening, brachydactyly, and mild craniofacial anomalies, such as flat forehead, protruding upper jaw, deep-set eyes, and thick eyebrows. Hearing and growth hormone levels were normal, and neuropathy was not reported. Vona et al. (2018) concluded that CAGSSS can show a wide range of clinical manifestations.

Clinical Variability

Takezawa et al. (2018) reported 2 Japanese sisters who presented at birth with poor overall growth and developed intractable seizures associated with hypsarrhythmia on EEG at 5 and 7 months of age. Brain imaging showed T2-weighted abnormalities in the basal ganglia, consistent with Leigh syndrome, as well as cortical atrophy. They had subsequent developmental arrest and became bedridden with hypotonic quadriplegia, but did not require mechanical ventilation. At age 8 and 5 years, respectively, both had severe short stature (-5.4 and -4.5 SD, respectively). Laboratory studies showed increased serum lactate, suggesting mitochondrial dysfunction. One patient was noted to have cataracts at 7.9 years, whereas the other did not have cataracts;. Other features, such as skeletal abnormalities, peripheral neuropathy, and hearing loss, were either not ascertained or not noted. However, Takezawa et al. (2018) concluded that the symptoms in these sibs fell within the spectrum of IARS2-related disorders.

Characterization of Skeletal Abnormalities

Mordaunt and Savarirayan (2015) questioned whether the skeletal dysplasia in the patients reported by Schwartzentruber et al. (2014) was a primary skeletal dysplasia, and suggested that it more likely was secondary to growth hormone deficiency and/or neuromuscular involvement. Mordaunt and Savarirayan (2015) noted that mitochondrial disorders are generally not considered to cause primary skeletal dysplasia. Samuels et al. (2015) responded that they considered the skeletal findings to be a fundamental component of the phenotype and noted that the skeletal changes appeared very early in the lives of the patients. The origin of the skeletal abnormalities cannot yet be determined.

Based on the phenotype of their patient, Moosa et al. (2017) concluded that the skeletal phenotype observed in this disorder was consistent with a primary skeletal dysplasia, particularly spondyloepimetaphyseal dysplasia (SEMD).

Ophthalmologic Findings

Jabbour and Harissi-Dagher (2016) described ophthalmologic findings in a 33-year-old French Canadian woman with CAGSSS, previously reported by Schwartzentruber et al. (2014). Best corrected visual acuities were 20/150 and 20/400 on the right and left, respectively. Her eyes demonstrated severe dryness, due to decreased tear production as well as marked corneal insensitivity. She had a history of multiple failed penetrating keratoplasties, with the right graft showing very mild subepithelial haze and the left graft showing diffuse haze with mild stromal edema. Optical coherence tomography revealed foveal hypoplasia. Jabbour and Harissi-Dagher (2016) noted that a hallmark of CAGSSS is infantile cataracts, presenting as diffuse haziness of the lens and associated with horizontal nystagmus. Another common feature is orbital myopathy, ranging from palpebral abnormalities such as ptosis to ocular misalignment and strabismus. In addition, all 3 patients with CAGSSS were born with clear corneas and developed central corneal opacities; the authors suggested that this might be due to neurotrophic keratopathy, as an extension of the distal sensory neuropathy of the disease, or could represent a separate manifestation of the mutated gene.

Inheritance

The transmission pattern of CAGSSS in the family reported by Liberfarb et al. (1993) and Schwartzentruber et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients, from a consanguineous kindred of French Canadian descent, with CAGSSS, Schwartzentruber et al. (2014) identified a homozygous missense mutation in the IARS2 gene (P909L; 612801.0001). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Patient fibroblasts showed a reduction in the IARS2 protein compared to controls; however, translation of mitochondrial proteins and analysis of oxidative phosphorylation complexes were similar to controls. Further functional studies were not performed.

In an 8-year-old Danish girl with CAGSSS, Moosa et al. (2017) identified a homozygous missense mutation in the IARS2 gene (G874R; 612801.0004). The mutation, which was found by whole-exome sequencing, was present in heterozygous state in the unaffected parents, confirming segregation with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

In 2 Japanese sisters with an unusual presentation of CAGSSS manifest as infantile-onset intractable seizures and Leigh syndrome (see 256000), Takezawa et al. (2018) identified compound heterozygous missense mutations in the IARS2 gene (F227S, 612801.0005 and R817H, 612801.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed, but immunoblot analysis of patient cells showed reduced IARS2 protein levels compared to controls.

In 3 patients from 2 unrelated consanguineous Iranian families with features consistent with CAGSSS, Vona et al. (2018) identified homozygous missense mutations in the IARS2 gene (P909S, 612801.0007 and H761R, 612801.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Cultured fibroblasts derived from the patient with the P909S mutation showed no obvious defects in mitochondrial respiratory chain function or protein levels. Functional studies and studies of patient cells from the other family were not performed.