Brain Malformations With Or Without Urinary Tract Defects

A number sign (#) is used with this entry because brain malformations with or without urinary tract defects (BRMUTD) is caused by heterozygous mutation in the NFIA gene (600727) on chromosome 1p31.

Some patients with a similar phenotype have larger deletions of chromosome 1p32-p31, including the NFIA gene; this disorder thus represents a contiguous gene deletion syndrome.

Clinical Features

Rao et al. (2014) reported an 8-year-old girl with BRMUTD. She presented at age 7 weeks with failure to thrive and jaundice, and was found to have abnormal craniofacial features, including overfolded helices, large head, metopic synostosis, upslanting palpebral fissures, and broad anteverted nose. At age 3 years, she showed delayed psychomotor development, hypotonia, poor hand/eye coordination, and articulation difficulties. She also had neuropsychologic problems, including attention-deficit hyperactivity disorder; she did not have seizures. Brain imaging showed partial absence of the septum pellucidum, hypoplastic corpus callosum, partial fusion of lateral ventricles, and ventriculomegaly. Urinary involvement included hydronephrosis, possible kinking of the pelviureteric junction, and a single unilateral renal calculus.

Negishi et al. (2015) reported a 5-year-old Japanese boy with BRMUTD. He was born with a large head (+3.3 SD), and brain imaging showed interhemispheric cysts, ventricular enlargement, and callosal agenesis; repeat brain imaging a few years later showed polymicrogyria. He had mildly delayed psychomotor development, but no seizures. He did not have significant dysmorphic features. Urinary involvement included hydronephrosis, cystectasia, and vesicoureteral reflux.

Nyboe et al. (2015) reported a family in which 3 sibs and their father had BRMUTD. Brain malformations included hypoplasia of the corpus callosum in all 4, ventriculomegaly in 3, herniation of the cerebellar tonsils in 2, absent falx cerebri in 1, and partial incomplete inversion of the left hippocampi in 1. Two members had renal defects, including 2 small cysts in one and unilateral hydronephrosis and hydrourethra, and a ureterocele in the other. All 4 had macrocephaly, and 3 had craniosynostosis, which was sagittal in 1 and lambdoid in 2. Three had developmental delay. Variable dysmorphic features included overgrowth, bilateral proximally placed first fingers, facial asymmetry, downslanting palpebral fissures, and low-set ears.

Chromosome 1p32-p31 Deletion Syndrome

Lu et al. (2007) reported 5 patients, including 2 half sibs, with a similar neurologic phenotype characterized by hypoplastic or absent corpus callosum, hydrocephalus or ventriculomegaly, and developmental delay. Four patients had a tethered spinal cord, 3 had Chiari type I malformation, and 3 had seizures. In addition, 3 patients had urinary tract defects, including vesicoureteral reflux and urinary incontinence. Other variable features included pigmentary retinopathy, inguinal hernia, cryptorchidism, and skeletal abnormalities, such as polydactyly and congenital hip dysplasia.

Koehler et al. (2010) reported a 6-month-old girl who presented with muscular hypotonia, macrocephaly, hypoplasia of the corpus callosum, and ventriculomegaly associated with a de novo microdeletion of chromosome 1p: del(1)(p32.2-p31.3). Dysmorphic features included a broad face with a broad, prominent forehead, low-set ears with dysplastic helices, concave profile of the nose, anteverted nostrils, small chin, small mouth with thin upper lip, high palate, sparse eyebrows, and cutis marmorata. There were no apparent renal, ureter, or skeletal abnormalities.

Labonne et al. (2016) reported follow-up of a 22-year-old woman (DGDP005) with chromosome 1p32 deletion syndrome who was originally reported by Zinner and Batanian (2003). She showed delayed developmental milestones in infancy, and later had cognitive impairment with attention deficit-hyperactivity disorder and obsessive-compulsive disorder. Craniofacial anomalies included macrocephaly, frontal bossing, low-set ears, narrow nose, and thin lips. Other features included ocular hypertension, sleep difficulties, and hypertonia. At age 22, she was diagnosed with subarachnoid and intraventricular hemorrhage as well as an intracerebral aneurysm. Microarray analysis identified a 9.45-Mb deletion at 1p32.2-p31.3 that included at least 35 genes, including NFIA. Analysis of patient cells showed significantly decreased expression of NFIA compared to controls.

Bayat et al. (2017) described a 9-year-old girl with macrocephaly, brain anomalies, and dysmorphic features who had a 1-Mb deletion of chromosome 1p32-p31. She had developmental and motor delay, facial dysmorphism including craniofacial asymmetry, downslanting palpebral fissures, low-set ears, and bilateral slightly broad and proximally placed first fingers. Her mother also carried the deletion and had macrocephaly, craniofacial asymmetry, low-set ears, a high palate, and bilaterally placed first fingers. Brain imaging in the proband showed hypoplastic corpus callosum, ventriculomegaly, loss of white matter, frontal cortical malformation with polymicrogyria and hypoplastic falx cerebri, partial inversion of the hippocampi, and arachnoid cysts. Brain imaging in the mother showed hypoplastic corpus callosum, mild ventriculomegaly, mild frontoparietal atrophy/hypoplasia, and slight asymmetry of the frontal gyri. Craniosynostosis and urinary tract anomalies were not present.

Cytogenetics

In 5 patients with hypoplastic or absent corpus callosum, hydrocephalus or ventriculomegaly, and developmental delay, Lu et al. (2007) identified balanced translocations or interstitial deletions of chromosome 1p31 involving the NFIA gene. The findings were confirmed by FISH and Southern blot analysis. Three of the patients had previously been reported by Campbell et al. (2002) and Shanske et al. (2004). Two half sibs had a 12-Mb deletion involving approximately 47 additional genes, and another patient had a 12-Mb deletion of chromosome 2q encompassing 39 additional genes, as well as a translocation involving chromosome 1p. The remaining 2 patients had a translocation with a microdeletion and a translocation, respectively. Although all 5 cases had haploinsufficiency of NFIA, each case also had involvement of 1 or more additional genes, which may have contributed to the phenotype. Intragenic mutations in the NFIA gene were not identified in any of the patients or in 219 additional patients with various neurologic developmental abnormalities. Lu et al. (2007) noted the phenotypic similarities to Nfia loss of function in the mouse and suggested that haploinsufficiency of the NFIA gene contributed to the malformation syndrome in these patients.

In a 6-month-old girl with macrocephaly, hypoplasia of the corpus callosum, and ventriculomegaly, Koehler et al. (2010) identified a 4.93-Mb deletion on the short arm of chromosome 1: del(1)(p32.2-p31.3), which deleted 16 genes, including the NFIA gene. Their case represented the smallest single imbalance deletion of this region reported to date.

Labonne et al. (2016) reviewed the features of several additional published and unpublished cases of patients with deletions in this region, and concluded that haploinsufficiency of the NFIA gene likely causes intellectual disability or cognitive deficits and macrocephaly. Haploinsufficiency of additional genes also likely contribute to the phenotype: these include DAB1 (603448), HOOK1 (607820), DOCK7 (615730), DNAJC6 (608375), and PDE4B (600127).

In a 9-year-old girl and her mother with macrocephaly, brain anomalies, and dysmorphic features, Bayat et al. (2017) identified a heterozygous 1-Mb deletion that included exons 1 and 2 of the NFIA gene. The deletion was found by array CGH and confirmed in the mother by quantitative PCR.

Molecular Genetics

In a girl with BRMUTD, Rao et al. (2014) identified a de novo heterozygous 120-kb intragenic deletion of the NFIA gene (600727.0001). The deletion was found by CGH microarray analysis. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a truncated protein and haploinsufficiency.

In a Japanese boy with BRMUTD, Negishi et al. (2015) identified a de novo heterozygous frameshift mutation in the NFIA gene (600727.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a truncated protein and haploinsufficiency.

In 4 members of a family with BRMUTD, Nyboe et al. (2015) identified a heterozygous 109-kb intragenic deletion affecting exons 1 and 2 of the NFIA gene (600727.0003).