Case 1: Failure to Thrive, Microcephaly, and Intracranial Calcifications in a 6-Week-Old Girl

This is the authors' abstract. We don't add key points for this paper.

A 6-week-old girl is admitted to the hospital for evaluation of failure to thrive. She is the first of twins, born at term to a primigravida mother. Pregnancy and delivery were uneventful. She weighed 2,490 g (less than the fifth percentile) at birth with a head circumference of 30 cm (less than the third percentile). On day 4 after birth, she developed episodes of choking and arching of her back associated with feeding. Different infant formula preparations were tried without any benefit. The parents are first cousins of Lebanese origin. Family history is noncontributory except for recurrent hand blisters in the father that erupt with cold weather.On examination, her vital signs are unremarkable. She weighs 2,780 g (less than the second percentile), her length is 49.5 cm (less than the second percentile), and head circumference measures 33 cm (less than the third percentile). No facial dysmorphism is seen. Neurologic examination reveals poor head control, appendicular hypertonia, and brisk deep tendon reflexes. Palmar and plantar grasps are present. The Moro reflex is symmetric. Funduscopic examination findings are normal. Cardiac auscultation reveals normal heart sounds without a murmur. The abdomen is soft and without hepatosplenomegaly.Laboratory examination reveals a normal complete blood cell count and transaminase levels. Computed tomography (CT) of the head reveals calcifications in the basal ganglia and in the deep white matter of the brain (Fig 1). The results of evaluation for TORCH (toxoplasmosis, other [syphilis, varicella-zoster, and parvovirus B19], rubella, cytomegalovirus, and herpes infections) infection, including serologic testing, urine culture, and blood polymerase chain reaction, are negative. Subsequent genetic testing reveals the diagnosis.Genetic testing noted homozygous deletions in the SAMHD1 gene on chromosome 20, confirming diagnosis of Aicardi-Goutières syndrome (AGS). Subsequent parental analysis revealed that the mother was heterozygous for the SAMHD1 mutation. The father tested homozygous for the deletion, which for him manifested with chilblain-lupus variant without neurologic involvement. The twin brother was also diagnosed as having AGS with a homozygous SAMHD1 deletion with subsequent developmental delay.AGS is a rare genetic encephalopathy, which was first described in 1984. The typical presentation is in early infancy, often after a period of normal development. Patients may present with irritability, disturbance in the sleep-wake pattern, and feeding difficulties. Many patients also develop unexplained recurrent fevers (sterile pyrexia). This is followed by a subacute regression of previously acquired milestones and a slowing of head growth (acquired microcephaly). The period of encephalopathy may last for several months, eventually leading to a phase where the disease progression appears to have halted. Approximately 40% of patients also develop chilblains on the toes and fingers.The neonatal form of the disease is seen in approximately 20% of patients with AGS. These patients have prominent neurologic dysfunction at birth or in the first few days of life. The clinical features include jitteriness, poor feeding, neonatal seizures, and microcephaly. They often have hepatosplenomegaly, elevated serum transaminase levels, anemia, and thrombocytopenia. The clinical syndrome thus closely resembles a congenital TORCH infection. However, hearing is usually preserved in AGS and chorioretinitis is not seen.Laboratory evaluation may reveal the presence of lymphocytosis in the cerebrospinal fluid (CSF) in the absence of infection. Elevated levels of CSF interferon-α and neopterin are present, especially in the early stage of the disease. The presence of these markers indicates an underlying central nervous system inflammatory process and is not specific for AGS. Nonetheless, in the presence of virologic studies with negative results, they are highly suggestive of AGS. Our patient had an elevated level of CSF neopterin. However, CSF leukocytosis was not present. The confirmatory diagnosis of AGS is by DNA mutation analysis, which reveals the presence of a causative mutation in 90% of the cases. AGS is genetically heterogeneous, with mutations in 5 genes: TREX1 (25%), RNASEH2A (40%), RNASEH2B (15%), RNASEH2C (5%), and SAMHD1 (5%). Transmission is predominantly by autosomal recessive inheritance. Although some genotype-phenotype correlation has been suggested, clinical heterogeneity may be seen with the same genetic abnormality as evident in the reported family.The phenotypic resemblance of AGS to congenital infections remains enigmatic. The current hypothesis suggests induction of an inflammatory process similar to that seen with a viral infection. Viral nucleic acids elicit a potent immune response due to their recognition as foreign proteins. Activation of the immune cells stimulates production of type 1 interferon and other cytokines, which play a role in the pathogenesis of neurologic defects attributed to congenital viral infections. This cascade is not activated by the endogenous self–nucleic acids, which are produced as a result of cellular metabolism, because they are normally broken down by nucleases. The genes involved in AGS may impair the formation of the nucleases. Thus, the endogenous nucleic acids produced by patients with AGS cannot be broken down and are capable of triggering an immune response. This interplay between a genetic mutation and an autoimmune neurodegenerative process is a unique feature of AGS. The immune-activation hypothesis of AGS is supported by the presence of chilblains, which are inflammatory lesions on the skin, and by detection of elevated CSF interferon-α.Imaging of the brain reveals the presence of intracranial calcifications as the cardinal feature of the disease. These calcifications are seen in most patients with AGS. The calcifications are most commonly located in the basal ganglia but could also be present in the deep white matter and cerebellum. Intracranial calcifications are not specific for AGS. A few important causes of intracranial calcifications in a newborn include congenital infections (human immunodeficiency syndrome and TORCH infection); hypoxic ischemic encephalopathy; endocrine disorders (hypoparathyroidism or hyperparathyroidism); inborn errors of metabolism, such as glutaric acidemia; neurocutaneous diseases (Sturge-Weber syndrome and tuberous sclerosis); and genetic syndromes (Cockayne syndrome). CT is the best modality to detect intracranial calcification and is superior to magnetic resonance imaging in most instances. Apart from the intracranial calcifications, brain imaging in children with AGS also reveals evidence of leukodystrophy and progressive cerebral atrophy.The long-term outcome of AGS is usually poor with residual neurologic impairment seen in most patients. Clinical manifestations that may be seen in the advanced stage of the disease include intellectual disability, spasticity, dystonia, truncal hypotonia, and poor head control. Epilepsy is seen in approximately 50% of the patients. Death usually occurs as a complication of the neurologic disability rather than actual disease progression. Patients with preserved intellectual function, although unusual, have been previously described in the literature.AGS has no specific treatment. Management consists of supportive measures, including treatment of epilepsy, management of spasticity, addressing risks of aspiration, dietary monitoring to ensure adequate calorie intake, and need for enteral tube feedings in advanced disease. Genetic counseling is a crucial aspect of management of the condition. If the mutation is identified in the index case, prenatal genetic diagnosis by chorion villus sampling or amniocentesis may be offered to the family.In conclusion, AGS should be strongly considered in newborns and infants when there are clinical features suggestive of a congenital infection in the absence of positive virologic study results.