Undifferentiated psychosis or schizophrenia associated with vermis-predominant cerebellar hypoplasia.

Schizophrenia (SCZ) is a well-studied neuropsychiatric condition that has been shown to have a high degree of genetic heritability. Still, little data on the specific genetic risk variants associated with the disease exists. Classification of the SCZ phenotype into SCZ-related endophenotypes is a promising methodology to parse out and elucidate the specific genetic risk variants for each. Here, we present a series of 17 previously reported individuals and a new proband with similar SCZ-related neuropsychiatric characteristics and shared brain imaging findings. Unsurprisingly, these individuals shared classic psychiatric features of SCZ. Interestingly, we also identified shared neuropsychiatric features in this series of individuals that had not been highlighted previously. A consistently decreased IQ, memory impairment, sleep and speech disturbances, and attention deficits were commonly reported findings. The brain imaging findings among these individuals also consistently showed posterior vermis predominant cerebellar hypoplasia (CBLH-V). Most individuals' diagnoses were initially described as Dandy-Walker malformation; however, our independent review of imaging suggests a more consistent pattern of posterior vermis predominant cerebellar hypoplasia rather than true Dandy-Walker malformation. While the specific genetic risk variants for this endophenotype are yet to be described, the aim of this paper is to present the shared neuropsychiatric features and consistent, symmetrical brain image findings which suggest that this subset of individuals comprises an endophenotype of SCZ with a high genetic solve rate.

Expanding the phenotypic spectrum of MPDZ gene variants: A case report with prenatally detected Dandy-Walker malformation and single ventricle heart.

A 19-year-old gravida underwent genetic counseling at the 26th week of gestation due to sonographically detected fetal anomalies, including Dandy-Walker malformation, characterized by cerebellar vermis hypoplasia and an enlarged cisterna magna, and single ventricle heart. Following amniocentesis at the 27th week, after the normal quantitative fluorescence polymerase chain reaction and chromosomal microarray results, trio clinical exome sequencing was performed, revealing a novel homozygous pathogenic variant in the MPDZ gene, c.4576G>T (NM_001378778.1). So far, homozygous and compound heterozygous variants in MPDZ have been strongly linked to congenital hydrocephalus type 2 with or without accompanying brain or eye anomalies. The reported variant, absent in control databases, resulted in premature termination of protein synthesis, consistent with pathogenicity predictions. Both parents were identified as heterozygous carriers. Pregnancy termination was chosen post-diagnosis. Postmortem findings correlated with prenatal ultrasound. Our case broadens the prenatal phenotypic spectrum associated with MPDZ variants, necessitating further studies for comprehensive understanding of molecular mechanisms beneath the clinical manifestations.

Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome.

Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease.

Clinical features and genetic analysis of Dandy-Walker syndrome.

BACKGROUND: Dandy-Walker syndrome (DWS) is a rare congenital malformation of the central nervous system (CNS), characterized by underdevelopment or dysplasia of the cerebellar vermis, expansion of the fourth ventricle and posterior fossa cistern. The incidence is aboutapproximately 1/25000-1/35000. At present, the etiology and pathogenesis of DWS are not completely clear. It is mostly considered to be a multifactorial genetic disease that is related to both genetic factors and environmental factors. There is no large sample size analysis of the chromosomal profile of DWS up to now. This study aims to provide clinical reference for prenatal diagnosis via summarizing the clinical features and pregnancy outcomes of Dandy-Walker syndrome. METHODS: A total of 76 cases of foetal Dandy-Walker syndrome out of 19,506 pregnant women underwent cordocentesis or amniocentesis for genetic detection. Rapid prenatal karyotyping, single nucleotide polymorphism array (SNP-array) and BACs-on-Beads™ (BoBs) were performed for prenatal genetic diagnosis. The results of ultrasonography, genetic analysis and pregnancy outcome were recorded. RESULTS: Of the 76 cases, 19 were isolated DWS, while 57 cases were accompanied by other ultrasound-visible abnormalities. Ultrasound abnormalities of the CNS were most frequently observed, accompanied by DWS. Twenty-five out of 76 cases had chromosomal abnormalities, and the rate of chromosomal abnormalities increased in pregnant women of advanced maternal age or in combination with other ultrasound abnormalities. Of the 19 cases in the isolated DWS group, nine pregnant women chose to terminate the pregnancy, while seven cases continued the pregnancy and all infants were normal. Among the 57 pregnant women with pathological ultrasound manifestations other than foetal DWS, 44 chose to terminate the pregnancy, while 12 cases continued the pregnancy. Further follow-up revealed one newborn with postnatal neurodevelopmental delay. A female term neonate presented with very severe sensorineural deafness, and an infant died 7 days after birth with abnormal development of multiple organs. CONCLUSIONS: Pregnant women with DWS in foetal ultrasonic examination should be offered a careful and comprehensive foetal ultrasound scan and further prenatal genetic testing including karyotype analysis and SNP-array. The prognosis of the foetus without chromosomal aberration is good in isolated DWS pregnancies but poor in nonisolated DWS pregnancies.

Relative prevalence and outcome of fetal posterior fossa abnormality.

AIM: To find out the relative incidence and outcome of posterior fossa abnormality (PFA) in terms of survival at birth until 2 years of age. METHODS: We conducted a prospective study; all fetuses diagnosed with posterior fossa abnormality were followed-up. The outcome was observed with respect to survival, the presence of associated anomalies, the existence of developmental delay after a telephonic interview. RESULTS: Out of 2703 children with congenital anomalies, 921 (34.1%) had a central nervous system defect; 76 cases of PFA were fully followed. Dandy-Walker malformation (DWM) was present in 50% (38/76), mega cisterna magna 18.4% (14/76), Blake pouch cyst 13.2% (10/76), vermian hypoplasia (VH) 13.2% (10/76) and arachnoid cyst 5.2% (4/76). The diagnosis was possible before 20 weeks in only 12 (15.8%) cases. The mean gestational age at delivery was 34.7 ± 6.7 weeks. Associated anomalies were seen in 35/76 (46.1%) cases. A total of 35/76 (46.1%) survived after 2 years; there was developmental delay in 9.2% of cases. CONCLUSION: There is a large variation in the outcome of PFA depending upon the type of anomaly. Associated anomalies are common in VH and DWM, making their prognosis worse.

Prenatal diagnosis of vermian cyst: a new type of posterior fossa cyst.

BACKGROUND: Prenatal diagnoses of cystic malformations of the posterior fossa mainly encompass arachnoid cysts, Blake's pouch cysts and Dandy-Walker syndrome. To date, vermian cysts have not been reported prenatally. OBJECTIVES: To report a series of fetuses with a vermian cyst. MATERIALS AND METHODS: This was a single-center retrospective study conducted from 2012 to 2021. We included all fetuses presenting with a vermian cyst and excluded all other types of posterior fossa cyst. The cyst was visible at prenatal ultrasound (US) and/or magnetic resonance imaging (MRI). Postnatal imaging and/or clinical outcome data were available. RESULTS: Sixteen fetuses fulfilled the inclusion criteria with a strong female predominance (n=13). US and MRI were performed at a mean gestational age of 29+5 and 33+1 weeks, respectively. In all patients, the cyst was in the vermian horizontal fissure. The mean longest dimension was about 10 mm. The vermis and other posterior fossa structures were otherwise normal. At postnatal imaging, 13 children underwent brain imaging including 11 MRIs with complete regression (n=9), stability (n=1) and increase in size (n=3) of the cyst. Psychomotor development was normal in 14 children. One child (with an inner ear malformation) showed a slight delay in walking and language acquisition. Slight walking ataxia was present in another child. CONCLUSION: We report 16 fetuses with posterior fossa cysts located within the vermis at the level of the horizontal fissure, diagnosed at US and/or MRI and carrying an overall excellent neurological prognosis.

Dandy-Walker malformation in methylmalonic acidemia: a rare case report.

BACKGROUND: Methylmalonic acidemia is an organic acid metabolism disorder that usually has nonspecific clinical manifestations. CASE PRESENTATION: A 3-month-old female infant was admitted to the hospital for developmental retardation. Her prenatal and birth history was unremarkable. After admission, she developed dyspnea and severe anemia and was subsequently transferred to the intensive care unit. Magnetic resonance imaging of her brain showed a Dandy-Walker malformation, and metabolic screening indicated methylmalonic acidemia. Thus, she was diagnosed with methylmalonic acidemia and Dandy-Walker malformation. The patient underwent treatment including acidosis correction, blood transfusion, antibiotics, mechanical ventilation and heat preservation. Unfortunately, her condition progressively worsened and she died of metabolic crisis. CONCLUSIONS: Dandy-Walker malformation may be a clinical manifestation of methylmalonic acidemia. Additionally, the co-existence of methylmalonic acidemia and Dandy-Walker malformation may be an uncharacterized syndrome which needs to be studied further.

Incidental Presentation of Dandy Walker Variant in 66 Year Male Patient.

Dandy-Walker variant consists of vermian hypoplasia and cystic dilatation of the fourth ventricle, without enlargement of the posterior fossa is a distinctive entity believed to represent a mild subtype of Dandy-Walker complex. We report a case of 66 year male presented with right sided hemiparesis due to ischemic stroke whose imaging showed incidental findings Dandy walker variant. This Incidental Dandy Walker malformation finding in adult is rare with only a few cases reported till date.

Hypoglycemia and Dandy-Walker variant in a Kabuki syndrome patient: a case report.

BACKGROUND: Kabuki syndrome (KS) is a rare congenital condition with cardinal manifestations of typical facial features, developmental delays, skeletal anomalies, abnormal dermatoglyphic presentations, and mild to moderate intellectual disability. Pathogenic variants in two epigenetic modifier genes, KMT2D and KDM6A, are responsible for KS1 and KS2, respectively. CASE PRESENTATION: A Chinese girl had persistent neonatal hypoglycemia and Dandy-Walker variant. Whole-exome sequencing identified a novel single nucleotide deletion in KMT2D (NM_003482.3 c.12165del p.(Glu4056Serfs*10)) that caused frameshift and premature termination. The mutation was de novo. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant is considered pathogenic. The patient was diagnosed with KS by molecular testing. CONCLUSION: A single novel mutation in KMT2D was identified in a KS patients with hypoglycemia and Dandy-Walker variant in the neonatal stage. A molecular test was conducted to diagnose KS at an early stage.

Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

BACKGROUND: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown. OBJECTIVE: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families. METHODS: Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype. RESULTS: We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure. CONCLUSION: We propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

[Genetic diagnosis of a fetus with Dandy-Walker syndrome].

OBJECTIVE: To explore the genetic basis for a fetus with Dandy-Walker malformation. METHODS: G-banding chromosomal karotyping, single nucleotide polymorphism microarray (SNP array) and fluorescence in situ hybridization (FISH) were carried out for the fetus. Chromosomal karyotyping and FISH assay were also carried out for both parents. RESULTS: SNP array has detected a 4266 kb microdeletion at 6p25.3p25.1 in the fetus, which was confirmed by FISH. FISH analysis of the parents demonstrated that the father has carried a cryptic t(6;14) (p25.1;p13) translocation, while the fetus has a der(6)t(6;14)(p25.1;p13) derived the paternal translocation. CONCLUSION: The der(6)t(6;14)(p25.1;p13) probably underlies the Dandy-Walker malformation in the fetus. The 6p25.3p25.1 microdeletion is due to unbalanced gametes produced by the father's cryptic balanced translocation.

NID1 variant associated with occipital cephaloceles in a family expressing a spectrum of phenotypes.

Autosomal dominant Dandy-Walker malformation and occipital cephalocele (ADDWOC) is a rare, congenital, and incompletely penetrant malformation that is considered to be part of the Dandy-Walker spectrum of disorders. Affected individuals often present with an occipital cephalocele with a bony skull defect, but typically have normal neurological development. Here, we report on a three-generation family in which individuals have variable phenotypes that are consistent with the ADDWOC spectrum: arachnoid cysts in the proband and his maternal grandfather, an occipital cephalocele in the proband and his brother, and a small bony defect in the proband's mother. Whole exome sequencing identified a rare heterozygous variant in NID1 (NM_002508.2:c.1162C>T, (p.Gln388Ter)) in the proband, his brother, and his mother. Sanger sequencing confirmed the presence of this variant in the maternal grandfather. The identical c.1162C>T variant was previously identified in variably affected members of a three-generation family with ADDWOC. This case report provides further evidence that variants in NID1 may be clinically relevant for the development of a phenotype that is consistent with ADDWOC, and extends the phenotype of NID1-associated ADDWOC to include arachnoid cysts. Given that the Dandy-Walker malformation itself is not a pre-requisite to this spectrum of phenotypes, we also suggest a novel term for the NID1-associated disorder in order to give emphasis to this phenotypic variability: "Autosomal Dominant Posterior Fossa Anomalies with Occipital Cephaloceles."

Dandy-Walker Malformation-Like Condition Revealed by Refractory Schizophrenia: A Case Report and Literature Review.

INTRODUCTION: Dandy-Walker malformation is a rare congenital malformation involving cystic dilatation of the fourth ventricle, enlarged posterior fossa, complete or partial agenesis of the cerebellar vermis, elevated tentorium cerebelli, and hydrocephalus. Previous research highlighted a possible role for the cerebellum in schizophrenia as well as the contribution of underlying brain malformations to treatment resistance. Here, we present a case of a Dandy-Walker malformation-like condition revealed by a refractory schizophrenia in a 24-year-old male patient. We also conduct a literature review of all previously published case reports or case series of co-occurring posterior fossa abnormalities and schizophrenia or psychosis using a PubMed search query to better understand the potential link between these two disorders. CASE PRESENTATION: A 9-month hospital stay was needed to address the treatment-resistant psychotic symptoms, and the patient continued to experience moderate symptoms despite the prescription of various antipsychotic and antidepressant medications. After an irregular initial medical follow-up, the patient is currently treated with 350 mg daily clozapine and 20 mg daily prazepam and still exhibits moderate anxiety without delirious thoughts, however allowing him to re-enroll at the university. Regarding the literature, 24 cases published between 1996 and 2017 were identified, reviewed and compared to the present case report. DISCUSSION: This case report and literature review further illuminates the pathophysiology of psychotic disorders including the potential role of the cerebellum, reinforces the importance of a multidisciplinary approach for the neurological and psychiatric management of patients with schizophrenia, and highlights optimal pharmacological management strategies for treatment-resistant schizophrenia.

The Impact of Prenatal Diagnosis of Selected Central Nervous System Anomalies for Prenatal Counselling Based on Significant Pregnancy Morbidity and Neonatal Outcomes.

BACKGROUND & OBJECTIVES: Prenatal screening and diagnostic imaging advances have led to an increased detection of CNS anomalies, including ventriculomegaly/congenital hydrocephalus (HCP), Dandy-Walker malformation (DWM), and myelomeningocele (MMC). Data on pregnancy outcomes and the impact of prenatal diagnosis on neonatal outcomes is limited. Our study aimed to provide data on obstetric and neonatal outcomes following prenatal diagnosis of one of three CNS anomalies. METHODS: A retrospective search of two databases in Alberta, Canada and NICU chart review of cases between 2001 and 2011was completed. Primary outcomes for each group were pregnancy outcome (live birth, stillbirth, and termination) and detection rate. Secondary outcomes were live and total birth prevalence, mode of delivery, GA at delivery, and length of NICU stay for inborn versus outborn patients. RESULTS: Prenatal detection rates were 91.6% (HCP), 83.4% (DWM), and 92.9 % (MMC). Termination rates were 30.2% (DWM), 34.2% (HCP), and 48.5% (MMC). Median GA (weeks, range) at diagnosis were 22 (17-38), 20 (12-37), and 20.5 (18-34) for HCP, DWM, and MMC, respectively. Rate of Caesarean section for fetal indication was 50.0%, 44.4%, and 42.9% for HCP, DWM, and MMC, respectively. Median NICU length of stay was longer for outborn patients than inborn patients and were as follows: (range) 33.0 (21-38) versus 8.5 (1-49) d (HCP), and 29 (29-57) versus 14 (2-75) d (DWM). CONCLUSION: This study provides termination rates, obstetric interventions, and NICU length of stay for prenatally-identified CNS anomalies. Collectively, this study assists prenatal counselling women with a fetus affected by a described CNS anomaly.

Prenatal diagnosis of posterior fossa anomalies: Additional value of chromosomal microarray analysis in fetuses with cerebellar hypoplasia.

OBJECTIVE: To elucidate the relationship between copy number variations (CNVs) detected by high-resolution chromosomal microarray analysis (CMA) and the type of prenatal posterior fossa anomalies (PFAs), especially cerebellar hypoplasia (CH). METHODS: This study involved 77 pregnancies with PFAs who underwent CMA. RESULTS: Chromosomal aberrations including pathogenic CNVs and variants of unknown significance were detected in 31.2% (24/77) of all cases by CMA and in 18.5% (12/65) in fetuses with normal karyotypes. The high detection rate of clinically significant CNVs was evident in fetuses with cerebellar hypoplasia (54.6%, 6/11), vermis hypoplasia (33.3%, 1/3), and Dandy-Walker malformation (25.0%, 3/12). Compare with fetuses without other anomalies, cases with CH and additional malformations had the higher CMA detection rate (33.3% vs 88.9%). Three cases of isolated unilateral CH with intact vermis and normal CMA result had normal outcomes. The deletion of 5p15, 6q terminal deletion, and X chromosome aberrations were the most frequent genetic defects associated with cerebellar hypoplasia. CONCLUSION: Among fetuses with PFA, those with cerebellar hypoplasia, vermis hypoplasia, or Dandy-Walker malformation are at the highest risk of clinically significant CNVs. Chromosomal microarray analysis revealed the most frequent chromosomal aberrations associated with CH.

Differential Diagnoses and Their Implications of Dandy-Walker Malformation or Isolated Cisterna Magna, a Case Study: Baby V.

We explore the outcome of a fetus with a posterior fossa abnormality thought to be a Dandy-Walker malformation based on prenatal ultrasound imaging. The infant was later diagnosed by magnetic resonance imaging (MRI) as having an isolated cisterna magna. When assessing brain abnormalities, there is increased accuracy of prenatal MRI versus prenatal ultrasound. Accurate diagnosis of an infant is paramount so that an inheritance pattern, risk of recurrence, involvement of other systems, and a prognosis can be determined. Communicating with the family and supporting them with the correct information is then enhanced. It should be standard protocol to obtain a fetal MRI if an abnormal prenatal ultrasound of the brain is detected. Further research is needed to assess the accuracy of using MRI versus ultrasonography prenatally to diagnose posterior brain abnormalities.

[Genetic analysis of two cases with Dandy-Walker deformed fetus].

OBJECTIVE: To explore the genetic etiology of two fetuses with Dandy-Walker malformation using single nucleotide polymorphism microarray (SNP-array). METHODS: The fetuses and their parents were subjected to G banding karyotype analysis. The fetuses were also subjected to SNP-array analysis. RESULTS: The parents of both fetuses showed a normal karyotype. One fetus has a 46,X,?i(X)(q10), while for another conventional cell culture has failed. SNP-array showed that one fetus carried a 6p25.3p25.2 microdeletion, and another carried a Xp22.33p22.2 deletion and a Yq11.221q11 duplication. The abnormal fragments have involved FOXC1, SHOX and STS genes, which are associated with Dandy-Walker malformation. CONCLUSION: Alteration of 6p25.3p25.2, Xp22.33p22.2 copy numbers probably underlies the Dandy-Walker syndrome in the fetuses. The disorder may be attributed to abnormal expression of FOXC1, SHOX, and STS genes. SNP-array can provide an important supplement for prenatal diagnosis.

A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.

Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc.

Risk factors for Dandy-Walker malformation: a population-based assessment.

Dandy-Walker malformation (DWM) is the most common congenital malformation of the cerebellum, but its causes are largely unknown. An increasing number of genes associated with congenital cerebellar malformations have been identified; however, few studies have examined the potential role of non-genetic, potentially modifiable risk factors. From the National Birth Defects Prevention Study, we examined maternal, paternal, and infant characteristics and maternal conditions and periconceptional exposures (from 1 month before to 3 months after conception) among infants with DWM (n = 160) and unaffected controls (n = 10,200), delivered between 1997 and 2009. Odds ratios, crude (cOR) and adjusted (aOR) were computed using logistic regression. Maternal factors associated with DWM included non-Hispanic black race/ethnicity (aOR = 2.0, 95%CI: 1.3-3.2). Among maternal conditions, a history of infertility increased the risk for DWM (all: aOR = 2.4, 95%CI: 1.3-4.6; multiple: aOR = 3.9, 95%CI: 1.7-8.9). The lack of association with many maternal exposures supports the hypothesis of a major contribution of genetic factors to the risk for DWM; however, the observed associations with maternal non-Hispanic black race/ethnicity and maternal history of infertility indicate that further research into factors underlying these characteristics may uncover potentially modifiable risk factors, acting alone or as a component of gene-environment interactions.