How to cite this article: Briggs TA, Wolf NI, D'Arrigo S, Ebinger F, Harting I, Dobyns WB, Livingston JH, Rice GI, Crooks D, Rowland-Hill CA, Squier W, Stoodley N, Pilz DT, Crow YJ. 2008. Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct “pseudo-TORCH” phenotype. Am J Med Genet Part A 146A:3173–3180.
Intracranial calcification (ICC) is a common pediatric neuroradiological abnormality, with intrauterine infection a frequent and important cause [Smith, 1992; Boppana et al., 1997; Lago et al., 2007]. Disturbance of calcium homeostasis and a number of well-defined genetic syndromes are also associated with this same feature [Aicardi, 1998]. Polymicrogyria (PMG) is a cortical malformation characterized by an excessive number of small gyri with abnormal cortical lamination. PMG may occur as an isolated focal abnormality, or as part of a more widespread disturbance of cortical genesis [Barkovich et al., 2005; Jansen and Andermann, 2005]. It is a heterogeneous disorder and can be seen in association with congenital infection [Barkovich and Lindan, 1994], but can also occur in the context of inherited disease [Jansen and Andermann, 2005].
The combination of ICC and PMG is unusual other than as a sequelae of congenital infection. Here, we report five children with a distinct pattern of ICC with PMG and simplified gyration all of whom were normocephalic at birth and demonstrated no congenital hepatosplenomegaly or thrombocytopenia. This phenotype represents a recognizable Mendelian mimic of congenital infection distinct from Aicardi-Goutières syndrome (AGS), and leads us to discuss the use of the term pseudo-TORCH syndrome, a diagnostic category recently removed from the OMIM catalogue.
This male was born to a nonconsanguineous white couple with no family history of note. He had an older maternal half-brother and sister. He was delivered at term by vaginal delivery in good condition with Apgar scores of 6 at 1 min and 9 at 5 min. His head circumference was 33.5 cm (10th centile) and his birth weight was 3.72 kg (50th centile). There were no immediate post-natal problems, he fed well and was discharged within 24 hr of birth. He presented at 1 week of age with two episodes of respiratory arrest. On each occasion he went cold and pale, began to sweat, took a few sharp respirations, stopped breathing and then went blue and floppy. These episodes lasted a few minutes after which he regained consciousness. On admission to hospital he was afebrile. His lower limb tone was thought to be possibly increased, but there were no other localizing neurological signs. Examination of his fundi was normal; in particular there was no evidence of chorioretinitis. Lumbar puncture showed a protein level of 0.06 g/L (normal range 0.04–0.4), 1 lymphocyte × 106/L and normal cerebrospinal fluid (CSF) lactate. The CSF appeared clear and there was no bacterial growth on long-term culture. A TORCH screen was negative. Urinary amino and organic acid screens were unremarkable. Hematological indices and liver function tests were consistently normal. An EEG was unremarkable. After this time he developed further seizures during which he would startle, abduct his arms, tremble and then cry. These episodes could occur singly or in clusters.
The child made almost no developmental progress. He was spoon fed initially but subsequently required a gastrostomy tube at the age of 5 years. He did not smile before the age of 3 years. He exhibited a profound microcephaly so that at 7 years of age his head circumference was 43 cm (6 cm below the 3rd centile). He developed a spastic quadraparesis with truncal hypotonia and had no useful volitional movement. At age 11 years he was severely handicapped. He was unable to sit unaided, showed contractures at the elbows, wrists, ankles and knees and had a mild scoliosis. He did not appear to respond to visual stimuli. Flash electroretinogram was normal, but visual evoked potentials and fundoscopy were suggestive of optic atrophy. The rest of the eye examination was normal. There was almost no verbalization although his parents felt that he did hear and would respond to music with moans and occasional laughter. He continued to have intermittent seizures. There were no abnormal skin markings and no chilblains or skin photosensitivity. He was non-dysmorphic and the rest of the physical examination was unremarkable. He died of unknown cause at age 11 years.
A cranial CT scan at age 2 weeks showed a band of calcification in the perisylvian regions with loss of gyration and gray white matter differentiation in the same areas evident on MRI (Figs. 1 and 2). Calcification was also present in the thalami and pons. The cerebellum appeared slightly hypoplastic.
At post mortem, his height was 127 cm (0.4th centile) and weight 35 kg (50th centile). Gross and histological abnormalities were confined to the brain. The ventricles were large and the corpus callosum thin. All areas showed widespread white matter loss, gliosis and cortical calcification (Fig. 3). Calcification occurred in a predominantly laminar pattern in the deep cortical layers, white matter and the basal ganglia and was frequently seen within blood vessel walls. Additionally, there was extensive PMG particularly involving the lateral aspects of the frontal and parietal lobes, that is in a perisylvian distribution.
This female is a younger full-sister of Patient 1, separated in birth-order from her brother by a normal female sibling. She was born at term by elective caesarean weighing 3.54 kg (75th centile). Her head circumference was 32 cm (2nd centile). Apgar scores were 9 at 1 and 9 at 5 min, but she was admitted to the special care unit because of some mild respiratory difficulty. On day 1 she developed startles consisting of a throwing out of the upper limbs and flexion of the legs followed by rhythmical arm movements. Her seizure activity was refractory to treatment and she spent most of the first year of life in the hospital. Chromosomes were normal, as was FISH analysis using a 17p probe specific for the Miller-Dieker locus. At the age of 5 months her head circumference was 37.5 cm (2.5 cm below the 3rd centile). She exhibited signs of a spastic quadriplegia. She fed poorly and had a gastrostomy tube inserted at the age of 12 months. Ophthalmological examination at age 2 years showed no abnormalities of ocular movement. The retinae were normal, although it was felt there was some pallor of the optic discs bilaterally. There was no evidence of useful visual function. There was decreased amplitude and delay of the visual evoked cortical responses. She made almost no developmental progress. She never laughed although she would occasionally smile from around the age of 4 years. There were no vocalizations beyond an infrequent moaning when she was ill. She weighed 20.3 kg (90th centile) at age 4 years. Six months later she developed pneumonia and died. A post mortem examination was declined.
Cerebral CT scan at age 2 months showed a ribbon of calcification in the posterior frontal, perisylvian, anterior temporal and anterior parietal areas evident on MRI scan as a band of low T1 and high T2 signal (Figs. 1 and 2). There was loss of gray-white matter differentiation in the same locations, with simplified gyration and a marked reduction of white matter throughout. A cortical dysplasia could not be confidently identified on the neuroimaging. Calcification was also present in both thalami, the basal ganglia and central pons. The cerebellum was slightly hypoplastic.
This female was the second child of unrelated Italian parents. She had a healthy older sister. She was born at term by spontaneous vaginal delivery after an uneventful pregnancy. Her birth weight was 3.078 kg (50th centile), length 50 cm (50th centile) and head circumference 33 cm (3–10th centile). Apgar scores were 8 at 1 min and 8 at 5 min. There were no immediate perinatal problems. Feeding difficulties were reported from 2 months of life. At age 3 months she experienced two generalized seizures on the same day. On clinical examination she was noted to have a head circumference of 35 cm (<3rd centile). EEG showed diffuse epileptic abnormalities during sleep, with sharp and slow-waves. CSF examination for protein, glucose and cells was normal. A TORCH screen was negative. Her epilepsy, characterized by one or two generalized seizures per month, was refractory to phenobarbital although she did show some response to sodium valproate. Between 3 and 20 months of life she experienced episodes of sterile pyrexia, 39.5–40°C, approximately once a month and lasting 7–10 days.
Over the first 2 years of life she developed a spastic-dystonic tetraparesis with no acquisition of motor skills. At age 24 months she was unable to control her head, language was absent and she smiled only occasionally. Head circumference was 40 cm (6 cm below the 0.4th centile). She was non-dysmorphic and there were no abnormal skin markings or chilblains. Further investigations including complement assays, autoantibody profile, calcium, phosphate, blood lactate and pyruvate, parathyroid hormone and karyotype were all normal. Mutation analysis of the AGS1-4 genes was negative.
A CT scan at age 24 months showed bilateral band-like calcification in the deep white matter of the frontal, anterior parietal and anterior temporal areas, the basal ganglia, thalami, and central pons (Fig. 1). Cerebral MRI scan confirmed a generalized reduction in white matter, and PMG of the posterior frontal, perisylvian and anterior parietal gray matter (Fig. 2).
This patient is the first child of consanguineous Turkish parents. He was born at term by spontaneous vaginal delivery after an uncomplicated pregnancy. His birth weight was 4.07 kg (75th centile), length 54 cm (75th centile) and head circumference 35.5 cm (50–75th centile). Apgar scores were 7 at 1 min and 9 at 10 min. Because of dyspnea and greenish appearing amniotic fluid, neonatal infection was suspected and antibiotic therapy initiated. During this time the child experienced three seizures. An EEG was normal and antiepileptic therapy was not started. At the age of 6 weeks the infant was readmitted with left focal clonic seizures and staring. EEG revealed focal epileptiform abnormalities especially over the right hemisphere. Antiepileptic therapy with oxcarbazepine and then topiramate was started, and seizures improved. We first saw the child at the age of 3 months. He had truncal hypotonia, absent head control, increased tone of arms and legs with increased tendon reflexes. He was unable to interact socially. He was experiencing 1–3 seizures per day with tonic posturing of the right arm, eye deviation to the right and then tonic-clonic movements of both legs. Later, seizure semiology changed to hypomotor seizures with nystagmus and cyanosis. Head circumference at this time was already microcephalic at 37 cm (1 cm <3rd centile), weight gain and growth being normal. His epilepsy was never controlled despite treatment with phenobarbital, valproate, levetiracetam, and bromide. At the age of 11 months a gastrostomy tube was inserted and at age 17 months he had a fundoplication because of severe gastro-oesophageal reflux with recurrent pneumonia. At that time, hypopigmented areas on the abdomen were noted which later disappeared. At the age of 2 years 9 months his head circumference was 41 cm (6.2 cm <3rd centile). The boy had made no developmental progress and demonstrated a severe spastic tetraparesis. EEG showed multifocal epileptiform abnormalities without normal background activity. At this same age he had several episodes of unexplained hypernatremia.
MRI examinations at the ages of 2 and 22 months showed widespread PMG, reduced white matter with periventricular calcifications and a small corpus callosum (Fig. 2). Cranial CT at the age of 2 years revealed coarse, confluent, band-like periventricular calcifications, calcification in the brainstem and symmetric calcifications in both thalami and cerebellar hemispheres (Fig. 1).
At the age of 6 weeks, CMV PCR in urine, CMV IgM and CMV pp65 antigen were positive with CMV IgG negative. At the age of 3 months IgG and IgM for CMV were positive. These results were most likely consistent with an early postnatal infection although, without CMV PCR testing of the Guthrie card, prenatal infection could not be ruled out. CMV DNA was not present in CSF, which showed an elevated protein (0.7 g/L; after a traumatic spinal tap) but with a normal cell count. Retinal examination was normal and the remaining TORCH screen was negative. Chromosomes were normal as was FISH analysis for a deletion at the Miller-Dieker locus.
This is the younger full-sister of patient 4. After an uneventful pregnancy, she was born at 38 weeks gestation by emergency caesarean indicated because of heart rate decelerations. Birth weight was 3.39 kg (25–50th centile), length 50 cm (25th centile) and head circumference 33 cm (10–25th centile). Apgar scores were 9 at 1 min and 9 at 10 min. At the age of 9 hr she experienced her first seizure, described as tonic-clonic with eye deviation, cyanosis, and bradycardia. Seizures did not respond to treatment with phenobarbital, pyridoxine, pyridoxal phosphate and folinic acid. We first saw the child at the age of 2 months. She was microcephalic with a head circumference of 34.3 cm (2.5 cm <3rd centile). Weight was on the 25th centile and length on the 50th centile. Head control was absent and tone in the arms and legs was increased, more so on the left side. Fixation was absent. She demonstrated hypomotor, clonic and automotor seizure types, frequently with cyanosis, which were refractory to treatment and more severe than in her brother.
MRI in the neonatal period demonstrated extensive PMG with probable calcifications (Fig. 2). Opercularization was abnormal. Cranial CT at age 3 months confirmed the coarse, band-like periventricular and thalamic calcifications (Fig. 1). There were no infratentorial calcifications.
Neonatal TORCH screening revealed positive IgG for CMV with absent IgM. CMV DNA was absent in urine. Organic acids in urine and amino acids in plasma and urine were normal. EEG showed multifocal epileptiform potentials with slowing over the left temporo-parietal region and severe background changes.
ICC and abnormal gyration are commonly seen in association with intrauterine infections [Marques Dias et al., 1984; Tovo et al., 1988; Hayward et al., 1991; Smith, 1992; Barkovich and Lindan, 1994; Steinlin et al., 1996; Boppana et al., 1997; Lago et al., 2007]. Consequently, it is not surprising that a clinical diagnosis of congenital infection was considered after the identification of abnormalities in Patient 1. However, the absence of serological confirmation of infection is of note, and our patients showed no evidence of hematological or hepatic derangement or chorioretinitis. Of particular interest in the five patients we report is the pattern of ICC, with a band-like, bilateral distribution, predominately affecting the anterior aspect of the cortex, thalami, and basal ganglia. We consider this pattern to be distinct from that usually seen in association with intrauterine infection where the calcification more typically involves the periventricular area and basal ganglia in a punctate distribution. Additionally, calcification was also seen in the central pons/brainstem in Patients 1, 2, 3, and 4—a feature which was absent in Patient 5. Polymicrogyria, predominately involving the posterior frontal, perisylvian and anterior parietal gray matter, was confirmed at post mortem in Patient 1 and identifiable on MRI in Patients 3, 4, and 5.
An absence in our patients of specific clinical and biochemical features allows for the exclusion of well characterized disorders in which ICC occurs in combination with PMG [Chitayat et al., 1992; Samson et al., 1994; Sakai et al., 1997] or separately as a major diagnostic sign [Aicardi and Goutières, 1984; Coskun et al., 1990; Aalfs and Hennekam 1995; al-Mane et al., 1998; Rapin et al., 2006; Thomas-Sohl et al., 2004; Renella et al., 2006; Saillour et al., 2007; Briggs et al., 2008].
A small number of reports [Burn et al., 1986; Reardon et al., 1994] have documented the combination of ICC and PMG with congenital microcephaly, hepatosplenomegaly, and thrombocytopenia where appropriate confirmatory tests for infectious agents have been negative (Table I). These cases bear similarity to our patients in regard to the presence of widespread cortical calcification and PMG, although they differ by demonstrating a prenatal onset of microcephaly, significant hepatic and hematologic derangement, and an absence of the band-like pattern of calcification seen in all five of our patients. We note also the singleton born to non-consanguineous parents described by Kalyanasundaram et al. 2003. Like our patients, this child showed band-like calcification with reduced gyration, the early onset of seizures and an absence of extraneurological features. However, of possible etiolgical significance, she experienced a prenatal onset microcephaly.
Table I. Summary of Cases in This Report and Other Congenital Infection-Like Cases Demonstrating the Combination of Intracranial Calcification With Polymicrogyria
The term pseudo-TORCH syndrome, also sometimes referred to as microcephaly intracranial calcification syndrome (MICS), has been used to denote a Mendelian phenotype comprising basal ganglia calcification with white matter changes and a reduction in brain size, apparently distinguishable from AGS on the basis of congenital (as opposed to post-natal) microcephaly, neonatal disturbance of liver function with thrombocytopenia, and a normal CSF white cell count [Reardon et al., 1994]. Clarification of the genetic basis of AGS and expansion of the AGS phenotype [Stephenson et al., 1997; Crow et al., 2000, 2003; Sanchis et al., 2005; Rice et al., 2007] suggests that this distinction is not appropriate so that the previous OMIM entry for pseudo-TORCH syndrome (251290) has been withdrawn and moved to the AGS (225750) entry. However, we note that a number of other congenital infection-like phenotypes, obviously distinct from AGS, have also been described [e.g., Slee et al., 1999; Vivarelli et al., 2001; Knoblauch et al., 2003; Gardner et al., 2005; Watts et al., 2008]. At present, the classification of these conditions is uncertain and so the use of the umbrella-term “pseudo-TORCH phenotype” may still be useful. The patients described in this report represent a clinically and radiologically recognizable subgroup of such Mendelian mimics of congenital infection.
We would like to thank Dr. Ulrich Seidel, Municipal Hospital Worms, for providing us with the MR images of Patient 5.