Microdeletion 1p32p31 Presenting with Moyamoya Disease and Incomplete Hippocampal Inversion

The chromosome 1p32p31 deletion syndrome (OMIM #613735) is a contiguous gene disorder with variable phenotype depending on the deletion size; the molecular basis seems to involve heterozygous mutation in or total/partial deletion of the nuclear factor I/A (NFIA) gene. It is clinically characterized by brain malformations with or without urinary tract defects, besides neurodevelopmental delay and dysmorphisms [1]. It was initially described by Lu et al. [2] and since then a few patients have been reported [3‒11]. Based on these additional findings, an expanded phenotype was proposed, including a previous report by Prontera et al. [12] of a patient presenting with moyamoya disease.

Neuroimaging was achieved in conventional MRI sequences (T1, T1 C + after injection of paramagnetic contrast medium/gadolinium, T2, FLAIR, SWI, and DWI/ADC map) and magnetic resonance angiography with a three-dimensional time-of-flight sequence. The imaging protocols were done in a PHILIPS imager, operating in a magnetic field of 1.5T, with acquisitions in the axial, sagittal, and coronal planes.

Chromosomal analysis was performed on G-banded metaphase cells, according to standard procedures, for the patient and his parents. Chromosomal microarray analysis of the patient was performed on DNA samples extracted from peripheral blood using the CytoScan 750K Array (Affymetrix, Santa Clara, CA, USA) following the manufacturer’s instructions. Data were analyzed using the Affymetrix Chromosome Analysis Suite (ChAS) version 3.1 (Affymetrix, Santa Clara, CA, USA).

The proband was the only child of a healthy, young, and non-consanguineous couple of mixed Brazilian origin. He was first seen at the age of 7 years and referred for clinical genetic evaluation due to hydrocephalus, renal malformation, and dysmorphisms.

Pregnancy was not planned, and a day-after pill was taken. There was delayed and decreased fetal movements, besides low amniotic fluid from the 2nd trimester. Delivery was at term by cesarean section due to abnormal progression of labor; measures were 3,250 g, 51 cm in length, and an OFC of 37 cm. A fast increase in the cephalic perimeter (41 cm) was noted on the 10th day of life. Follow-up showed nonhypertensive hydrocephalus and a late bregmatic fontanelle closure at the age of 28 months.

Recurrent infections of the urinary tract were seen between ages 6 months and 3 years, and abdominal ultrasound investigation showed pyelocaliceal dilatation of mild degree at right and moderate at left kidneys, resulting in a left megaureter; DMSA renography at age 8 years demonstrated preserved tubular function. Neurodevelopmental milestones were borderline, and at school age, he presented learning disabilities, being referred to a school for children with special needs at the age of 9 years.

The clinical genetic evaluation revealed the following dysmorphisms (Fig. 1): macrocephaly, high frontal bossing, low posterior hairline, low set and dysmorphic ears, hypertelorism, narrow palpebral fissures, laterally curved eyebrows, long eyelashes, malar flattening, broad and depressed nasal bridge, anteverted nares, downturned corners of the mouth, high arched palate, long fingers, proximal set thumbs, excessive creases in the palms, short 2nd, 4th, and 5th metacarpals, long toes, hallux valgus, toepads, clinodactyly of the 4th and 5th toes, mild penoscrotal transposition, and coronal hypospadia.

Complementary investigation included thyroid function tests, ophthalmological evaluation, ECG and echocardiogram, hand bone age, and spine radiographic study – all within the normality. Brain CT scans from ages one to 6 years showed persistence of cavum septum pellucidum and a moderate supraventricular system dilatation.

At the age of 11 years, he started to present with movement disorder (chorea) and absence seizures managed, respectively, with haldol and valproic acid treatment. Investigation included antistreptolysin O titer, lactate levels, blood gas, HPLC quantification of organic acids, serum homocysteine, serum ceruloplasmin, 24-h urinary copper excretion, and screening for lysosomal storage disorders with glycosaminoglycans and oligosaccharides chromatography, all within normal results; chitotriosidase activity was increased (483 nMol/h/mL; reference range 8.8–132).

At the age of 18 years, he presented a sudden left-sided hemiparesis episode, including facial hemiparesis and worsening of the choreic movement disorder; neuroimaging revealed an ischemic stroke, moyamoya disease, and bilateral incomplete hippocampal inversion (IHI) (Fig. 2, 3). A superficial temporal artery to middle artery bypass revascularization surgery was performed with partial recovery of movements and speech, besides better sialorrhea and seizure control. One year after that, he presented a new sudden episode of dysarthria, behavioral stop, and a 50-min postictal somnolence state. Neuroimaging discharged a recent stroke, and EEG revealed a nonconvulsive status epilepticus pattern; clinical control was obtained when the valproic acid dosage was adjusted. EEG was compatible with temporal intermittent rhythmic delta activity.

A previous G-banding chromosomal analysis revealed an apparently normal male karyotype, 46,XY. The chromosomal microarray analysis showed a deletion of 13.2 Mb at 1p32.3p31.2 (genomic position: 55,716,252-68,934,595; hg19), encompassing 53 protein-coding genes, including 50 registered in the OMIM database. Initially, the deletion missed in G-banding and seen after it was identified by aCGH; the careful reanalysis of the patient’s karyotype revealed the deletion at 1p32p31 and both parents had a normal karyotype (Fig. 4).

Lu et al. [2] described five individuals presenting a new condition of central nervous system (CNS) malformations (abnormalities of the corpus callosum, hydrocephalus/ventriculomegaly, type I Chiari malformation) associated with urinary tract defects (mainly vesicoureteral reflux), besides developmental delay and seizures; two of them presented balanced translocations disrupting the NFIA gene and three had interstitial microdeletions involving the same gene. These authors suggested the role of NFIA as causative of this new disorder based on murine models [13] and later supported by further reports of additional patients presenting similar clinical pictures and intragenic deletions of several exons [4, 7, 14] or loss-of-function mutations caused by missense, nonsense, and frameshift variant sequences [8, 15].

Lu et al. [2] did not detail dysmorphism in their report. Still, a pattern of craniofacial features was described in other reports and comprised macrocephaly, high forehead, low set, and dysmorphic ears, upslanting palpebral fissures, broad nose with anteverted nares, downturned corner of the mouth, and high palate. Other described features include craniosynostosis [4, 7] and polymicrogyria [7]. Neurodevelopment was variable from normal or borderline to cerebral palsy, absent speech, and autism spectrum disorder. Vertical transmission was also seen in a few families [2, 3, 7, 8]. Additionally to those cases, a contiguous gene syndrome caused by microdeletions of the 1p31.3p32.2 region where NFIA is located was described by Koehler et al. [16], with further reports [3, 5, 6, 10, 12].

An expanded phenotype based usually in individual cases includes ambiguous genitalia and intrauterine growth restriction [3, 9], cryptorchidism, seizures, heart defects [5], choanal atresia, sensorineural hearing loss, microcephaly, low total and LDL cholesterol [10], temporal lobe epilepsy and schizoaffective disorder [11]. Those features are variable depending on the size and gene content of the deletion, thus probably reflecting the haploinsufficiency of other genes involved in the phenotype. Most cases with microdeletions involving the NFIA gene presented with CNS abnormalities, especially hypoplasia of the corpus callosum and ventriculomegaly (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000535240); microdeletions in this region that do not involve the NFIA gene do not present those features, or no CNS abnormalities at all. The current patient’s deletion overlaps with all previous reported patients with partial or total deletions of NFIA and CNS malformations (online suppl. Fig. 5).

Of particular interest is the report of Prontera et al. [12] from a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion overlaps totally with the deletion in the present case and encompasses 34 protein-coding genes, including NF1A and the OMIM-annotated genes C8A, C8B, TACSTD2, ANGPTL3, FOXD3, ALG6, and PGM1. The patient exhibited a combination of features compatible with this microdeletion syndrome. At the age of 10 years, he presented an episode of right-sided weakness due to acute ischemic stroke of the basal ganglia bilaterally; 1 year later, during a febrile episode, he experienced a tonic-clonic seizure involving the right upper limb and brain MRI associated with cerebral angiography revealed the typical “puff of smoke” aspect of moyamoya disease.

The authors question if moyamoya may be due to the haploinsufficiency of a gene in the 1p32p31 region as a starting point for future investigations of its genetic aspects [12]. Focus was given to the Forkhead box D3 (FOXD3) gene due to its function and its analogy to another FOX gene (FOXC1) that was found to be duplicated in another patient presenting with juvenile moyamoya. In addition, this patient had moderate bilateral conductive hearing loss, dysmorphisms, and developmental delay, presenting with acute left-sided hemiparesis and left-sided facial droop after a fever episode. She had a complex chromosome rearrangement, including a duplication of 14.2 Mb at 6p25.3p23, encompassing the FOXC1 gene [17].

Moyamoya disease is a chronic, non-inflammatory, and non-atherosclerotic cerebrovascular occlusive disease characterized by progressive stenosis of the terminal portion of the internal carotid artery and its main branches, resulting in abnormal formation of collateral vessels. It manifests clinically as ischemic or hemorrhagic stroke with high rates of morbidity and mortality. Its etiology and pathophysiological triggers remain unknown and probably include immune, genetic, and inflammatory factors [18, 19].

Based on a few reports of familial aggregation, some candidate loci are listed as possibly related to moyamoya, including the MYMY1 locus that maps to chromosome 3p and four other susceptibility loci caused by variation in the RNF213 gene on chromosome 17q25 (MYMY2), 8q23 (MYMY3), the ACTA2 gene on chromosome 10q23 (MYMY5), and the GUCY1A3 gene on chromosome 4q32 causing moyamoya with achalasia (MYMY6). An X-linked recessive syndromic disorder characterized by moyamoya disease, short stature, hypergonadotropic hypogonadism, and facial dysmorphism it is caused by a contiguous gene deletion syndrome at Xq28 (MYMY4) [1].

Recently, a study of 88 pediatric MMA patients, which performed molecular karyotyping and exome sequencing, described deleterious variants mainly in the RNF213 and NF1 genes. Also, pathogenic copy number variants were found, including an Xq24 rearrangement, a 16p11.2 deletion together with a gain in 1q21.1-21.2, a 15q11.2 BP1-BP2 duplication, and a deletion in 1p36.22 [20]. Only a small deletion in one patient was found in the 1p31.3 region, including the AK4 gene. This gene is also deleted in our patient and the patient described by Prontera et al. [12]. The AK4 is an Adenylate Kinase, which belongs to a family of structurally and functionally related enzymes that are important for maintaining homeostasis of the adenine and guanine nucleotide pools [21]. However, no disease has been associated with this gene.

IHI, also known as malrotation, is an atypical anatomical pattern of the hippocampus, which has been reported in healthy subjects in different studies [22‒24]. However, it has been described in patients with epilepsy, severe midline malformations, and other brain malformations. IHI is associated with distinct developmental defects, such as agenesis of the corpus callosum [25], and patients with several genetic disorders, including microdeletion syndromes [26‒29]. The patient described by Nyboe et al. [14] also presented a partial incomplete inversion of the left hippocampi and showed a 109 kbp deletion encompassing exons 1 and 2 of the NFIA gene, indicating that this gene is involved in such feature. So, IHI is likely a marker of more extensive atypical development that may render the brain more susceptible to pathological mechanisms.

In conclusion, chromosome 1p32p31 deletion syndrome is a rare disorder with few reports in the literature and an expanded phenotype still under delineation. This is the second report of a patient who developed moyamoya disease and the first to describe bilateral IHI in this microdeletion syndrome.

CES is the local research group coordinator of the Rede Nacional de Doenças Raras (RARAS), a multicentric research project funded by the National Council for Scientific and Technological Development and the Brazilian Ministry of Health (CNPq/MS/SCTIE/DECIT N° 25/2019). The metabolic investigation was performed through the Rede EIM Brasil network, HCPA/UFRGS. The authors kindly thank the patient and his parents for their cooperation.

This study was conducted following the Declaration of Helsinki and approved by the Ethics Committee Board of the State University of Campinas (CAAE number 33970820.0.3014.5404). Written informed consent and photograph permission were obtained from the patient’s mother.

The authors have no conflicts of interest to declare.

The research conducted in this study was not supported by any grant.

C.E.S. guided conception and oversight of manuscript development and critically reviewed the manuscript for intellectual content; R.P.O.S. and L.M.B. collected clinical data and reviewed literature; J.L.H. and F.R.R.A. analyzed data; F.R. collected and analyzed neuroimaging data; T.P.V. analyzed cytogenetic and cytogenomic data; all authors reviewed the manuscript for intellectual content and approved the final manuscript as submitted.

The data supporting this study’s findings are available from the corresponding author upon reasonable request.