Ichthyotic Keratoderma, Spasticity, Hypomyelination, And Dysmorphic Facial Features

A number sign (#) is used with this entry because of evidence that ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features (IKSHD) is caused by heterozygous mutation in the ELOVL1 gene (611813) on chromosome 1p34.

Description

Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity (Mueller et al., 2019). In addition, patients exhibit mild facial dysmorphism (Kutkowska-Kazmierczak et al., 2018).

Clinical Features

Kutkowska-Kazmierczak et al. (2018) reported 2 unrelated Polish boys, aged 13 years (patient 1) and 4 years (patient 2), who both exhibited progressive skin dryness with hyperkeratosis and lower extremity spasticity. Other features included rotary nystagmus and sensorineural deafness, as well as mild facial dysmorphism, with wide eyebrows, long nose with bulbous tip, long philtrum, full lips, and relatively large ears. Intellectual development was normal. Brain MRIs showed globally impaired myelination, supra- and infratentorially; MRI at age 13 years in patient 1 showed slight atrophic progression involving the cerebral hemispheres and corpus callosum. The older boy was wheelchair-dependent, but the younger could walk with orthoses. The authors designated the disease to be a syndrome of 'ichthyotic keratoderma, spasticity, mild hypomyelination, and dysmorphic features (IKSHD).'

Independently, Mueller et al. (2019) studied the same 2 Polish boys reported by Kutkowska-Kazmierczak et al. (2018), ages 15 (patient 1) and 5 years (patient 2), who had dry, scaly, and thickened skin over the entire body, particularly over extensor joints, with hyper- and hypopigmented areas. Parents in both families mentioned an intermittent 'strange' body odor. The older patient also had thickened fingernails that split into horizontal layers; palms, soles, scalp, and mucous membranes were spared. Biopsy of affected skin from patient 1 showed ichthyosis, with thickening of the stratum corneum and spinosum, and electron microscopy revealed numerous lysosomes filled with lipopigment. Both patients also had progressive high frequency hearing deficit with onset in the first decade of life, and both exhibited horizontal nystagmus. Patient 1 had marked photophobia, progressive difficulty with night vision, and visual field constriction. Spectral domain-optical coherence tomography (SD-OCT) showed thinning of the peripapillary retinal nerve fiber layer in both patients; electroretinographic responses were normal. Both patients were wheelchair-dependent and had dysarthric speech. Neurologic examination of patient 1 at age 14 years revealed hyperreflexia, upgoing plantar reflexes, contractures of large joints, and equinovarus foot deformity. His arms were less severely affected, but showed some some contractures and muscle atrophy, although he was an elite wheelchair athlete. Patient 1 also reported intermittent stool incontinence and incomplete bladder voiding, and urodynamic investigation showed neurogenic bladder with detrusor-sphincter dyssynergia. Cranial MRIs showed nonprogressive hypomyelination in the posterior limb of the internal capsule and in the optic radiation in both patients, and somatosensory and acoustic evoked potentials were consistent with a brainstem and central conduction defect.

Molecular Genetics

In 2 unrelated Polish boys with IKSHD, Kutkowska-Kazmierczak et al. (2018) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the ELOVL1 gene (S165F; 611813.0001). Calculation of kinship coefficient indicated no relationship between the 2 families, which was confirmed by analysis of ultra-rare variants other than the ELOVL1 mutation.

Mueller et al. (2019) independently studied the same 2 Polish boys with IKSHD reported by Kutkowska-Kazmierczak et al. (2018), and also identified heterozygosity for S165F in ELOVL1. Segregation analysis demonstrated that the variant arose de novo in both patients; founder haplotype analysis excluded a common ancestral origin of the mutation.