The Neuropathology of 1p36 Deletion Syndrome: An Autopsy Case Series

Abstract

1p36 deletion syndrome is the most common terminal deletion syndrome, manifesting clinically as abnormal facies and developmental delay with frequent cardiac, skeletal, urogenital, and renal abnormalities. Limited autopsy case reports describe the neuropathology of 1p36 deletion syndrome. The most extensive single case report described a spectrum of abnormalities, mostly related to abnormal neuronal migration. We report the largest published series of 1p36 autopsy cases, with an emphasis on neuropathologic findings. Our series consists of 3 patients: 2 infants (5-hours old and 23-days old) and 1 older child (11 years). Our patients showed abnormal cortical gyration together with a spectrum of neuronal migration abnormalities, including heterotopias and hippocampal abnormalities, as well as cerebellar hypoplasia. Our findings thus support the role of neuronal migration defects in the pathogenesis of cognitive defects in 1p36 deletion syndrome and broaden the reported neuropathologic spectrum of this common syndrome.

INTRODUCTION

1p36 deletion syndrome is thought to be the most common subtelomeric microdeletion syndrome, with an estimated frequency of 1 in 5000 to 10 000 live births (1, 2). Patients have abnormal facies, microcephaly, and developmental delay, with frequent cardiac, skeletal, urogenital, and renal abnormalities (3). The severity of the clinical phenotypes depends, at least in part, on the size and location of the 1p36 deletion (2). Limited case reports of autopsies from patients with 1p36 deletion syndrome, most in autolyzed fetuses, describe polymicrogyria with limited assessment of other features (4, 5). A single report of complete autopsy neuropathology in a patient with 1p36 deletion described a number of malformations, including micrencephaly, periventricular nodular heterotopia, callosal hypoplasia, hippocampal malrotation, and cortical dysgenesis resembling polymicrogyria (3).

Because the neuropathology of 1p36 deletion syndrome has been described only in limited case reports, the full spectrum of neuropathologic changes is not well-characterized. We report neuropathologic findings in 3 cases of 1p36 deletion syndrome, consisting of 2 neonates and 1 older child. Our findings represent, to our knowledge, the largest published autopsy series of this common cause of intellectual disability.

MATERIALS AND METHODS

All cases reported were obtained through the autopsy service at the University of Iowa Hospitals and Clinics (UIHC). Autopsy consent was obtained from the next of kin for hospital autopsies and under the authority of the appropriate county medical examiner for forensic cases. The systemic autopsies were conducted under the supervision of board-certified anatomic pathologists (J.B. and M.N.). Brains were removed in the usual fashion and fixed in 20% formalin for 7–10 days prior to dissection. All normal ranges reported are from those previously reported by Molina et al (6). Paraffin-embedded tissue was processed in the usual fashion, and all stains were performed in the Department of Pathology at UIHC. Gross examination, dissection, and histologic examinations were performed by or under the supervision of a board-certified neuropathologist with experience in pediatric and developmental neuropathology (M.M.H.).

RESULTS

Case #1

The patient was an 11-year-old Caucasian female born at 38 weeks. Pregnancy was complicated by poor fetal growth and maternal tobacco and marijuana use. She was small for gestational age at birth and had Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Physical examination in infancy revealed microphthalmia, short palpebral fissures with deep-set eyes, and poor tracking. Infantile spasms began at 4 months of age. An MRI of the brain performed at that time demonstrated left fronto-parietal polymicrogyria (Fig. 1A). The frontal and parietal white matter showed increased T2 signal with decreased T1 signal, left greater than right, suggestive of delayed myelination (Fig. 1B). Microarray testing revealed a deletion of the p-arm of chromosome 1 distal to 1p36.3.

FIGURE 1.

Neuroradiologic and neuropathologic findings in Case #1. (A) T2-weighted MRI showing left-sided polymicrogyria (arrowheads). (B) T1 FLAIR and T2 showing increased T2 and decreased T1 suggestive of delayed myelination. (C) Coronal sections of fixed brain at the level of the nucleus accumbens and (D) at the level of the pulvinar nucleus and hippocampus showing polymicrogyria (arrowheads), an enlarged inferior horn of left lateral ventricle (white arrow), and a small left lateral geniculate nucleus with adjacent ectopic gray matter within the posterior limb of internal capsule (black arrow).

At age 5, she scored below first percentile on all domains of the Vineland Adaptive Behavior Scales and at a 5-month level on the Bayley Scales of Infant and Toddler Development. She remained non-verbal, unable to walk unassisted, and unable to follow commands. She underwent surgical repair of a peri-membranous ventricular septal defect at age 8 and spinal fusion for neuromuscular scoliosis at age 9. Precocious puberty developed at age 9. At her last neurologic examination prior to her death, she was having seizures approximately once per week on Phenobarbital, remained non-verbal, and was able to crawl and sit independently. The cause of death was accidental drowning in a bathtub at age 11 years.

Systemic autopsy findings included a perimembranous ventricular septal defect and dysplastic aortic valve, status post patch closure of the ventricular septal defect, diffuse enlargement and nodular hyperplasia of the thyroid gland without a discernable isthmus, evidence of early onset puberty and residual thoracic scoliosis status post posterior spinal fusion with rod placement. There was abundant hemorrhagic froth in the lungs, consistent with the patient’s history of drowning.

The brain weighed 950 grams [95% confidence interval (CI) for age 1102–1640]. Gross examination showed multiple abnormalities of neuronal migration, including peri-sylvian, left frontal and temporal polymicrogyria, and multiple neuronal heterotopias (Fig. 1C, D). Microscopically, these regions showed thinned and hyperconvoluted cortex, with fusion of the molecular layer, consistent with the gross impression of polymicrogyria. The hippocampi were mildly asymmetric, with an enlarged inferior horn of the left lateral ventricle (Fig. 1D). The left lateral geniculate nucleus was markedly smaller than the right, with an adjacent area of ectopic gray matter within the posterior limb of the internal capsule (Fig. 1D). Although delayed myelination was noted on MRI during infancy (see above), myelination of the corresponding areas was grossly normal at autopsy. All posterior fossa structures were grossly and microscopically unremarkable.

Case #2

The patient was a 23-day-old term female neonate born at 37 weeks gestation weighing 1625 grams. Pregnancy was complicated by prenatal diagnosis of fetal anomalies including congenital heart disease, cleft lip and palate, and intrauterine growth restriction. Prenatal cytogenetic testing detected a 1p36 deletion, but information on the size and exact location of the deletion was not available. Labor was induced at 37 weeks due to abnormal umbilical Dopplers and intrauterine growth restriction. Amniotic fluid was meconium stained. Apgar scores were 6 and 8 at 1 and 5 minutes, respectively.

Examination revealed cleft lip and palate, a systolic murmur, and hypotonia. Echocardiography at birth revealed a dysplastic tricuspid valve, severe right atrial dilation, moderate right ventricle dilation, and multiple muscular ventricular septal defects. On day of life 2, a brain ultrasound showed apparent agenesis of the corpus callosum with associated colpocephaly. She required mechanical ventilation and was started on inhaled nitric oxide on day of life 6. After failed indomethacin closure, she underwent surgical PDA ligation. Her postnatal course was complicated by worsening respiratory failure and biventricular heart failure. She died on day of life 23.

Systemic findings at autopsy included cleft lip and palate, a dysplastic tricuspid valve, severe right atrial dilation, moderate right ventricle dilation, and multiple ventricular septal defects. The brain weighed 276 grams (95% CI for age 258–576). The corpus callosum was abnormally thinned and malformed. Subtle gyral abnormalities were present on the medial surface of the frontal and parietal lobes, along the cingulate sulcus, and in the occipital lobe along the calcarine fissure (Fig. 2A). There was an area of hyperconvoluted gyri in the left inferior frontal lobe (Fig. 2B). The cerebellum was hypoplastic (Fig. 2B, C) and, microscopically, multiple focal abnormalities of neuronal migration were seen. The right inferior frontal lobe, corresponding to the region of hyperconvoluted gyri, showed fused gyri without other evidence of abnormal cortical lamination. Immature neuronal heterotopias were present in the basal ganglia. The cerebellum was hypoplastic, but the microscopic architecture of the folia was preserved. There were scattered gray matter heterotopias in the cerebellar white matter, composed of nodules of disorganized granular cells with intermixed Purkinje-like cells. The inferior olivary nucleus was abnormally formed, consisting of scattered islands of haphazardly arranged neurons (Fig. 2D). There were also multiple sequelae of her congenital heart disease and resulting hypoxic-ischemic injury, including multifocal periventricular leukomalacia, diffuse white matter gliosis and focal gliosis, and neuronal loss in the lateral thalamus.

FIGURE 2.

Neuropathologic findings in Cases #2 and #3. In Case #2 (A), the corpus callosum was thin and malformed (arrow). Apparent areas of absent corpus callosum represent artifactual disruption. Subtle gyral abnormalities were seen on the medial surface of the frontal and parietal lobes along the cingulate sulcus and in the occipital lobe along the calcarine fissure. (B) Additionally, here was an area of hyperconvoluted gyration in right inferior frontal lobe (arrow). The cerebellum was hypoplastic. (C) A comparison infant brain of similar age (12 days) is presented to illustrate the small cerebellar size in Case #2. (D) The inferior olivary nucleus was malformed, consisting of scattered islands of haphazardly arranged neurons rather than a convoluted strip. (E) In Case #3, microscopic examination of the pre-central gyrus with abnormal gyration showed multifocal areas with irregular undulating or festooning of cortical layer II (arrows). (F) Sections of hippocampus showed abnormal formation of Ammon’s horn consisting of a nodule of unoriented mature neurons (arrow).

Case #3

The patient was a 5-hour-old preterm neonate born at 33 weeks 2 days gestation who died of complications of Tetralogy of Fallot. Birth weight was 1355 grams (small for gestational age) with head circumference of 26.5 cm, less than 5th percentile for age and sex. Prenatal chromosomal microarray demonstrated a 16.0 mb terminal deletion from 1p36.33 to 1p36.13. Autopsy findings were significant for dysmorphic facial features including dolichocephaly, retrognathia, broad nasal tip and bridge, low-set and posteriorly-rotated ears, and bilateral absence of the superior crus of the ears with over folding of the cartilage of the right ear.

The brain weight was not recorded. Multiple gross gyral abnormalities were noted. Specifically, there was abnormal gyration of the pre-central and post-central gyri, consisting of smooth, flattened areas and adjacent hyperconvoluted areas. The superior temporal gyrus was small compared to the adjacent gyri.

Microscopic examination showed multiple focal abnormalities of neuronal migration. A section of the grossly abnormal precentral gyrus showed large regions of undulation in cortical layer II, (Fig. 2E). Ammon’s horn was abnormally formed, with a distinct nodule of mature neurons without laminar architecture (Fig. 2F).

DISCUSSION

These 3 patients with 1p36 deletion syndrome show a spectrum of malformations, which, in keeping with previous case reports, are characterized predominantly by abnormal neuronal migration. All 3 cases demonstrated evidence of polymicrogyria, as well as other neuronal migration abnormalities such as heterotopias and hippocampal malformations. Several findings, such as festooning of the supragranular layers and cerebellar hypoplasias, are consistent with those reported by Shiba et al. in their detailed neuropathologic description of a patient with 1p36 deletion syndrome (3). Therefore, while the spectrum of abnormalities is broad, some characteristic features seem to be common. Our findings thus support the role of neuronal migration defects in the pathogenesis of cognitive defects in 1p36 deletion syndrome.

The 2 patients with detailed cytogenetic data had deletions in the reported distal critical regions thought to be responsible for the syndrome’s neurodevelopmental manifestations (7). The older child (Case #1) with the longest survival had a smaller (2.4 mb) deletion limited to 1p36.32, compared to the neonatal case with cytogenetic data (Case #3). Previous studies have not clearly established the extent of association between deletion size and clinical phenotype (8).

Most published descriptions of 1p36 deletion-associated abnormalities are based on radiologic findings. (9). Fregeau et al described 10 patients with alterations in RERE, a gene at the proximal region of 1p36, who shared a clinical phenotype that overlapped with patients with 1p36 deletions. Imaging findings in those patients included thinning of the corpus callosum, ventriculomegaly, and decreased myelination (10). Other radiologic studies have described periventricular nodular heterotopias (11) and unilateral perisylvian polymicrogyria (9). These radiologic findings generally overlap with the neuropathologic findings seen in our cases (Table).

TABLE.

Described Cases of 1p36 Deletion Syndrome or RERE Alterations with Radiologic or Neuropathologic Characterization

Author/Year	No. of Cases	Age(s)	Genetic Alteration	Modality	Neuropathologic and Radiologic Findings
Fregeau et al. (2016)	10	4 months–14 years	RERE alterations	MRI	Abnormalities of the corpus callosum Diminished white matter volume Abnormalities of the cerebellar vermis Ventriculomegaly
Descartes et al. (2011)	1	2 months	Monosomy 1p36 19p13.3 trisomy	MRI	Periventricular nodular heterotopias
Saito et al. (2011)	1	3 months	Monosomy 1p36	MRI	Asymmetric bilateral perisylvian polymicrogyria
Shiba et al. (2013)	1	10 years	Monosomy 1p36	Autopsy	Cortical dysgenesis resembling polymicrogyria Periventricular nodular heterotopia Micrencephaly Hippocampal malrotation Superiorly rotated cerebellum with small vermis Callosal hypoplasia
Campeau et al. (2008)	1	21 weeks gestation	Monosomy 1p36	Autopsy	Hydrocephalus Posterior interhemispheric ventricular cyst Focal polymicrogyria Cerebellar hypoplasia
Faivre et al. (1999)	1	24 weeks gestation	Monosomy 1p36	Autopsy	Dilation of the left ventricle Polymicrogyria of the left lobe
Current study	3	23 days–11 years	Monosomy 1p36	Autopsy	Polymicrogyria Multiple neuronal heterotopias Abnormal formation of Ammon’s horn Cerebellar hypoplasia

Three autopsy cases have been reported in the literature, including 2 fetuses and one 10-year-old child. The 2 fetal cases both had limited neuropathologic examination due to autolysis. Both reports described polymicrogyria, and one reported cerebellar hypoplasia (4, 5). The third reported autopsy case was a 10-year-old child who showed periventricular nodular heterotopias, polymicrogyria, hippocampal malrotation, and callosal hypoplasia (3). Our oldest case (11 years) had findings similar to those of the previously reported 10-year-old. Because we were fortunate to have well-preserved fetal and neonatal specimens, we were able to characterize the early developmental stage of these abnormalities.

The identification of 1p36 deletions in each case strongly supports the conclusion that these neuropathologic findings result from the pathogenicity of the deletion. However, one case showed significant hypoxic-ischemic injury, and we cannot definitively exclude a role for antenatal or perinatal ischemic injury in the development of some lesions. Additionally, some findings, such as cerebellar heterotopias, may be seen in normal infant brains and cannot definitively be proven to be pathologic.

Although we report the largest autopsy cohort to date, our study is limited by its retrospective nature, small number of cases, and the lack of detailed cytogenetic data in some cases. These limitations also make it difficult to correlate the size of the deletion and involvement of particular genes or size of deletion with specific individual neuropathologic findings. Some investigators have suggested the phenotype of RERE gene mutations is similar to that of 1p36 deletions, suggesting that at least part of the 1p36 deletion phenotype may be due to loss of this gene (10). Detailed mapping of individual genes and their role in this complex phenotype will require systematic clinical, radiologic, and pathologic studies in a larger number of patients.

We present the largest reported series of autopsied patients with 1p36 deletion syndrome and describe a spectrum of neuropathological findings, which are predominantly related to abnormal neuronal migration during development. Our findings thus confirm and broaden the spectrum of described neuropathologic abnormalities in these patients.

 

The authors have no conflicts of interest to declare.

 

This work was supported in part by grants from the National Institutes of Health (UL1TR002537, K23NS109284), the Iowa Neuroscience Institute, and the Roy J. Carver Trust to M.M.H