Sanchis et al. (2005) described 2 brothers, born of second-cousin parents of white Spanish ancestry, who had intrauterine growth retardation and clinical features suggestive of intrauterine infection but with negative bacteriologic and serologic investigations. At birth, the older ... Sanchis et al. (2005) described 2 brothers, born of second-cousin parents of white Spanish ancestry, who had intrauterine growth retardation and clinical features suggestive of intrauterine infection but with negative bacteriologic and serologic investigations. At birth, the older brother was microcephalic with left peripheral facial paralysis and dysmorphic features including hooked nose with low-set anteriorly rotated ears. He had respiratory insufficiency requiring oxygen, hepatosplenomegaly, and spontaneous tremors with muscle tone shifting from hyper- to hypotonic. He did not cry, and he had reduced reflexes with absent sucking reflex. He developed clonic seizures a few hours after delivery. Cerebral ultrasonography and computed tomography demonstrated enlarged ventricles with abundant pericallosal calcifications, which also affected the thalamus, cerebellum, and brainstem. Brain MRI showed cerebral, cerebellar, and brainstem atrophy, with simplification of the gyri, predominantly of the frontotemporal lobes. Electroencephalogram revealed asymmetric interhemispheric and subcortical paroxysmal activity. Anemia, leukopenia, and thrombocytopenia were present, but resolved after 2 months of age; elevated liver enzymes persisted. At 7 years of age, the patient had short stature and was underweight and microcephalic. He exhibited severe psychomotor retardation with signs of bilateral spasticity affecting the upper and lower limbs, and continued to have seizures. He was unable to sit and had no speech. He died of pneumonia at 7 years of age. The younger brother also had microcephaly noted at birth, with dysmorphic features similar to those of his older brother as well as splenomegaly, hypertonicity, and seizures; he also had recurrent apneic episodes associated with generalized hypotonia and bradycardia for the first 2 weeks of life. He had mild anemia, moderate leukopenia, and a normal platelet count. Cerebral CT showed hydrocephalus; calcifications of the basal ganglia, internal capsule, cerebral cortex, and cerebellar white matter and peduncles; and cerebellar and mesencephalic atrophy. Cerebrospinal fluid showed lymphocytosis and elevated interferon-alpha (147660), and he had elevated liver enzymes. Examination at 13 months of age showed significant psychomotor retardation with little spontaneous movement and clonic movements in response to tactile stimuli; he did not visually fix or follow.
In 2 brothers with Aicardi-Goutieres syndrome from a consanguineous family of Spanish ancestry reported by Sanchis et al. (2005), Crow et al. (2006) identified a homozygous mutation in the RNASEH2A gene (606034.0001).
Rice et al. (2007) ... In 2 brothers with Aicardi-Goutieres syndrome from a consanguineous family of Spanish ancestry reported by Sanchis et al. (2005), Crow et al. (2006) identified a homozygous mutation in the RNASEH2A gene (606034.0001). Rice et al. (2007) found RNASEH2A mutations in 3 of 127 pedigrees with a clinical diagnosis of AGS. Four children in these 3 families had biallelic mutations. Four of 5 mutations, 1 of which occurred in homozygous form, were missense. The patient with the homozygous mutation, who was affected at birth and required immediate support, died at 7 years of age. In 1 family Rice et al. (2007) identified a single mutation in RNASEH2A that had been inherited. In a cohort of 251 families with a clinical diagnosis of AGS, Rice et al. (2013) identified 4 probands with synonymous mutations in the RNASEH2A gene, R25R (606034.0002) or V23V (606034.0004), present either in homozygosity or in compound heterozygosity with missense mutations (606034.0003-606034.0006). Their unaffected parents were each heterozygous for 1 of the mutations. Functional analysis confirmed the pathogenicity of the synonymous mutations.