X-linked Dominant Inheritance Pattern Research Articles

Clinical case of Wieacker–Wolff syndrome in a 5-year girl

Wieacker–Wolff syndrome (WWS) (OMIM 314580, 301041) is rare, slowly progressive, X-linked hereditary disorder. It is characterized by fetal akinesia, which results in congenital multiplex arthrogryposis, spasticity, and development delay. WWS is caused by the point mutations or extended deletions in the ZC4H2 gene, located on the long arm of the X chromosome (Xq11.2). Currently, about 100 cases have been described.
 We present the case of WWS 5-year girl. DNA diagnostic was performed using full exome sequencing and confirmed by Sanger sequencing. Determination of non-random X-chromosome inactivation was performed by methyl-sensitive PCR of GAAA-repeat RP2 gene. 
 The main clinical symptoms in our case are stiffness of large and small joints, specific facial phenotype, spasticity and lack of independent walking. We revealed heterozygous mutation с.22_23delAT (p.Met8fs) in ZC4H2 gene. Non-random inactivation of the X chromosome was detected (XCI = 96.1%).
 Conclusions. Clinical symptoms of the disease, the nature of the detected mutation and the literature data indicate to the presence of an X-linked dominant pattern of inheritance of WWS in our patient. We described the case referred to the group of ZC4H2-associated rare disorders.

MED12 variants associated with X-linked recessive partial epilepsy without intellectual disability

ObjectivesThe MED12 gene encodes mediator complex subunit 12, which is a component of the mediator complex involved in the transcriptional regulation of nearly all RNA polymerase II-dependent genes. MED12 variants have previously been associated with developmental disorders with or without nonspecific intellectual disability. This study aims to explore the association between MED12 variants and epilepsy. Materials and methodsTrios-based whole-exome sequencing was performed in a cohort of 349 unrelated cases with partial (focal) epilepsy without acquired causes. The genotype-phenotype correlations of MED12 variants were analyzed. ResultsFive hemizygous missense MED12 variants, including c.958A>G/p.Ile320Val, c.1757G>A/p.Ser586Asn, c.2138C>T/p.Pro713Leu, c.3379T>C/p.Ser1127Pro, and c.4219A>C/p.Met1407Leu were identified in five unrelated males with partial epilepsy. All patients showed infrequent focal seizures and achieved seizure free without developmental abnormalities or intellectual disability. All the hemizygous variants were inherited from asymptomatic mothers (consistent with the X-linked recessive inheritance pattern) and were absent in the general population. The two variants with damaging hydrogen bonds were associated with early-onset seizures. Further genotype-phenotype analysis revealed that congenital anomaly disorder (Hardikar syndrome) was associated with (de novo) destructive variants in an X-linked dominant inheritance pattern, whereas epilepsy was associated with missense variants in an X-linked recessive inheritance pattern. Phenotypic features of intellectual disability appeared as the intermediate phenotype in terms of both genotype and inheritance. Epilepsy-related variants were located at the MED12-LCEWAV domain and the regions between MED12-LCEWAV and MED12-POL. ConclusionMED12 is a potentially causative gene for X-linked recessive partial epilepsy without developmental or intellectual abnormalities. The genotype-phenotype correlation of MED12 variants explains the phenotypic variations and can help the genetic diagnosis.

Phenotypic overlap between cardioacrofacial dysplasia-2 and oral-facial-digital syndrome

Oral-facial digital (OFD) syndrome is characterized by abnormalities of the face (hypertelorism and low set-ears), oral cavity (multiple frenula, lingual hamartoma, or lobulated tongue) and extremities (postaxial polydactyly). At least 19 genes have been implicated in the development of OFD syndrome. Herein, we report the case a 13-year-old patient with atrioventricular septal defect, moderate intellectual disability, epilepsy, and features of OFD, including multiple oral frenula, and postaxial polydactyly of the hands and feet. The patient had a de novo heterozygous variant in PRKACB: chr1(GRCh37):g.84700915T > C, c.1124T > C (NM_182948.4), p.(Phe375Ser). To date, four patients with pathogenic monoallelic variants in PRKACB have been reported, and the condition associated with these variants is referred to as Cardioacrofacial dysplasia-2 (CAFD2, MIM619143). Previously reported features of this condition include congenital heart disease (e.g., atrioventricular septal defect) and postaxial polydactyly, and two of the patients had multiple oral frenula. We suggest that a significant phenotypic overlap exists between CAFD2 and OFD syndrome, in that these patients especially share the features of postaxial polydactyly and multiple oral frenula. The phenotypic similarity between patients with CAFD2 and classic OFD syndrome with an OFD1 variant might be explained by the recent in vitro experimental finding that a protein kinase A subunit encoded by PRKACB directly phosphorylates the OFD1 protein. From the standpoint of genetic counseling, OFD syndrome type1, the prototypic form of OFD, exhibits an X-linked dominant inheritance pattern, whereas other forms of OFD syndrome exhibit an autosomal recessive inheritance pattern. Recognition of CAFD2 as a differential diagnosis or forme fruste of OFD syndrome suggests that an autosomal dominant pattern of inheritance should also be considered during genetic counseling.

Genetic epilepsy caused by CDKL5 gene mutations as an example of epileptic encephalopathy and developmental encephalopathy: literature review and own observations

The disease caused by mutations in the CDKL5 gene (encoding cyclin-dependent kinase 5, CDK5) belongs to the group of early (infantile) epileptic encephalopathies caused by alterations in the genome. Currently, the disease is called “developmental encephalopathy and epileptic encephalopathy type 2”. This disorder is a complex combination of symptoms that develop due to deficiency or absence of the CDKL5 gene product, which is serine/threonine kinase. The CDKL5 gene is located on X chromosome; the disease has an X-linked dominant inheritance pattern. This literature review summarizes relevant studies analyzing the disease caused by CDKL5 gene mutations, including its genetic and epidemiological aspects, clinical manifestations, characteristics of epilepsy, principles of diagnosis, and therapeutic approaches. We present a case series of several patients with genetic disorders involving the CDKL5 gene.

Aberrant Splicing in GJB1 and the Relevance of 5' UTR in CMTX1 Pathogenesis.

The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5′ untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5′ UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels.

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population.

To decipher the genotype-phenotype correlation of auditory neuropathy (AN) caused by AIFM1 variations, as well as the phenotype progression of these patients, exploring the potential molecular pathogenic mechanism of AN. A total of 36 families of individuals with AN (50 cases) with AIFM1 variations were recruited and identified by Sanger sequencing or next-generation sequencing; the participants included 30 patients from 16 reported families and 20 new cases. We found that AIFM1-positive cases accounted for 18.6% of late-onset AN cases. Of the 50 AN patients with AIFM1 variants, 45 were male and 5 were female. The hotspot variation of this gene was p.Leu344Phe, accounting for 36.1%. A total of 19 AIFM1 variants were reported in this study, including 7 novel ones. A follow-up study was performed on 30 previously reported AIFM1-positive subjects, 16 follow-up cases (53.3%) were included in this study, and follow-up periods were recorded from 1 to 23 years with average 9.75 ± 9.89 years. There was no hearing threshold increase during the short-term follow-up period (1-10 years), but the low-frequency and high-frequency hearing thresholds showed a significant increase with the prolongation of follow-up time. The speech discrimination score progressed gradually and significantly along with the course of the disease and showed a more serious decline, which was disproportionately worse than the pure tone threshold. In addition to the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is also observed in AIFM1-related AN and affects females. In conclusion, we confirmed that AIFM1 is the primary related gene among late-onset AN cases, and the most common recurrent variant is p.Leu344Phe. Except for the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is another probability of AIFM1-related AN, with females affected. Phenotypical features of AIFM1-related AN suggested that auditory dyssynchrony progressively worsened over time.

011–X-Linked Hypophosphatemia (XLH): New Knowledge for Nurses Regarding Genetics, Pathophysiology and Clinical Presentation

Background: Over 80 years ago Fuller Albright reported a vitamin D-resistant form of rickets, which is likely the initial description of X-linked hypophosphatemia (XLH). Recently the genetic basis of the disease has been identified and a more complete understanding of the pathophysiology has emerged. Purpose: To increase awareness of the latest published data on the genetics, clinical manifestations, differential diagnoses, biochemical findings, as well as growth and development of patients with XLH. Description of Topic: XLH is a rare, progressive, life-long disorder and the most common form of heritable rickets. The estimated prevalence of XLH is 1:20,000 to 1:25,000. XLH is caused by loss-of-function mutations in the phosphate regulating endopeptidases on the X-chromosome (PHEX) gene, leading to high circulating levels of fibroblast growth factor 23 (FGF23). Over 300 PHEX mutations have been reported. An X-linked dominant inheritance pattern is typical; however, de novo PHEX mutations are reported in up to 20-30% of the cases. Excess FGF23 increases urinary phosphate losses with consequent hypophosphatemia, resulting in rickets and osteomalacia. Clinical manifestations may include lower limb deformities, short stature, bone and joint pain, dental abscesses, delayed walking, and gait abnormalities. Neurological features may include Chiari 1 malformation and craniosynostosis. Low serum phosphate levels, a low renal tubular threshold for phosphate reabsorption (TmP/GFR), and low or normal circulating 1,25(OH)2D are characteristic biochemical findings in patients with XLH. The symptoms of XLH vary among individuals and while there is similar pathophysiology for children and adults, clinical manifestations can differ. Debilitating consequences in adults include osteoarthritis, enthesopathy, spinal stenosis and pseudofractures. In addition, complications of conventional medical therapy (phosphate salts and active vitamin D analogs) include nephrocalcinosis and hyperparathyroidism. Clinical Implications: Previously, XLH was considered a disorder that manifests only during growth; however, adolescent patients require attention along with a smooth transition to adult care. In addition, recognition of the complex disease features of XLH is essential for accurate diagnosis and management. Pediatric endocrine nurses are well qualified to provide the latest disease state education to patients and families, and to encourage routine clinical evaluation to assess treatment response, disease progression, and therapeutic complications.

A Case of Familial Focal Dermal Hypoplasia: A Report of 3 Cases in Consecutive Generations

Focal dermal hypoplasia (FDH), or Goltz syndrome, is a rare multisystem disorder affecting mesodermal and ectodermal structures, with the skin, eyes, teeth, and musculoskeletal systems most commonly affected. FDH results from mutations in the PORCN gene. Ninety-five percent of cases arise from novo mutations, whereas 5% are hereditary with an X-linked dominant inheritance pattern. Here, we describe an uncommon presentation of FDH in three consecutive generations. Patient 1 is an 8-month-old female born of non-consanguineous marriage who presented with diffuse alopecia of the scalp, linear hypopigmented, atrophic papules, and plaques with peripheral hyperpigmentation on the left hemiabdomen and right lateral leg along Blaschko's lines as well as syndactyly of the right second and third toes. Skin biopsy from the abdomen showed a thin epidermis with flattened rete ridges and massive dermal edema within collagen fibers and reactive capillaries. Family history was significant for similar skin lesions and bone deformities in her mother and similar skin lesions in her grandmother. Patient 2 (patient 1’s mother) is a 17-year-old female with similar linear hypopigmented, atrophic plaques with peripheral hyperpigmentation on the abdomen and right axilla, syndactyly of the right hand, patchy alopecia of the scalp, microdontia, teeth fusion, enamel defects, verrucous papillomas in the axillae and onycholysis. Patient 3 (patient 1’s grandmother), presented with similar hypopigmented, atrophic plaques on the abdomen and left arm.

Four-Generation Pedigree of Monozygotic Female Twins Reveals Genetic Factors in Twinning Process by Whole-Genome Sequencing.

Familial monozygotic (MZ) twinning reports are rare around the world, and we report a four-generation pedigree with seven recorded pairs of female MZ twins. Whole-genome sequencing of seven family members was performed to explore the featured genetic factors in MZ twins. For variations specific to MZ twins, five novel variants were observed in the X chromosome. These candidates were used to explain the seemingly X-linked dominant inheritance pattern, and only one variant was exonic, located at the 5'UTR region of ZCCHC12 (chrX: 117958597, G > A). Besides, consistent mitochondrial DNA composition in the maternal linage precluded roles of mitochondria for this trait. In this pedigree, autosomes also contain diverse variations specific to MZ twins. Pathway analysis revealed a significant enrichment of genes carrying novel SNVs in the epithelial adherens junction-signaling pathway (p = .011), contributed by FGFR1, TUBB6, and MYH7B. Meanwhile, TBC1D22A, TRIOBP, and TUBB6, also carrying similar SNVs, were involved in the GTPase family-mediated signal pathway. Furthermore, gene-set enrichment analysis for 533 genes covered by copy number variations specific to MZ twins illustrated that the tight junction-signaling pathway was significantly enriched (p < .001). Therefore, the novel changes in the X chromosome and the provided candidate variants across autosomes may be responsible for MZ twinning, giving clues to increase our understanding about the underlying mechanism.

X-linked dominant protoporphyria: a new porphyria

X-linked dominant protoporphyria (XLDPP) was first reported in the genetics literature in 2008. It has a phenotype very similar to erythropoietic protoporphyria (EPP), but is distinguished from EPP by higher concentrations of erythrocyte protoporphyrin (of which a high proportion is zinc-chelated), its apparently higher incidence of liver disease, and an X-linked dominant pattern of inheritance. Dermatologists should understand how XLDPP differs from EPP, in order to advise newly diagnosed patients correctly about the genetic implications and the long-term management strategy. We present a case series of XLDPP to introduce this condition to the dermatology literature.

Incontinentia pigmenti

Incontinentia pigmenti is a rare genodermatosis in which the skin involvement occurs in all patients. Additionally, other ectodermal tissues may be affected, such as the central nervous system, eyes, hair, nails and teeth. The disease has a X-linked dominant inheritance pattern and is usually lethal to male fetuses. The dermatological findings occur in four successive phases, following the lines of Blaschko: First phase - vesicles on an erythematous base; second phase - verrucous hyperkeratotic lesions; third phase - hyperchromic spots and fourth phase - hypochromic atrophic lesions.

Median Facial Cleft Dysmorphism in Three Siblings: Case Report and Review of the Literature

Cleft of the facial midline is an extremely rare entity, occurring in probably less than 1 per 100,000 births (Kawamoto and Patel, 1998). Median facial cleft may present with a wide spectrum of features, including hypertelorbitism, V-shaped frontal hairline, bifid cranium, broad nasal root, bifid nose, median cleft of the upper lip, and median cleft of the premaxilla (Urata and Kawamoto, 2003). This condition is most commonly known as a 0–14 cleft, as classified by Tessier (1976), but multiple other classifications and terminologies have been proposed (DeMyer, 1963; Sedano et al., 1970; Cohen, 1982; van der Meulen et al., 1983; Kawamoto and Patel, 1998). In this article, we will refer to all cases as median facial cleft dysmorphism, as suggested by Kawamoto and Patel (1998). Genetic inheritance is most commonly sporadic, with other reported cases suggesting an autosomal dominant or Xlinked dominant inheritance pattern. We report three cases of median facial cleft dysmorphism, all of which occurred in siblings of the same family; we describe the clinical features and give support to the published literature suggesting an autosomal dominant inheritance pattern.

Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations

We identified four girls with a consistent constellation of facial dysmorphism and malformations previously reported in a single mother-daughter pair. Toe syndactyly, telecanthus and anogenital and renal malformations were present in all affected individuals; thus, we propose the name 'STAR syndrome' for this disorder. Using array CGH, qPCR and sequence analysis, we found causative mutations in FAM58A on Xq28 in all affected individuals, suggesting an X-linked dominant inheritance pattern for this recognizable syndrome.

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

Genetic basis of Rett syndrome.

The origin of Rett syndrome has long been debated, but several observations have suggested an X-linked dominant inheritance pattern. We and others have pursued an exclusion-mapping strategy using DNA from a small number of familial Rett syndrome cases. This work resulted in the narrowing of the region likely to harbor the mutated gene to Xq27.3-Xqter. After systematic exclusion of several candidate genes, we discovered mutations in MECP2, the gene that encodes the transcriptional repressor, methyl-CpG-binding protein 2. Since then, nonsense, missense, or frameshift mutations have been found in at least 80% of girls affected with classic Rett syndrome. Sixty-four percent of mutations are recurrent C > T transitions at eight CpG dinucleotides mutation hotspots, while the C-terminal region of the gene is prone to recurrent multinucleotide deletions (11%). Most mutations are predicted to result in total or partial loss of function of MeCP2. There is no clear correlation between the type and position of the mutation and the phenotypic features of classic and variant Rett syndrome patients, and XCI appears to be a major determinant of phenotypic severity. Further research focuses on the pathogenic consequences of these mutations along the hypothesis of loss of transcriptional repression of a small number of genes that are essential for neuronal function in the maturing brain.

Mapping a Dominant Form of Multinodular Goiter to Chromosome Xp22

Multinodular goiter (MNG) is a common disorder characterized by a nodular enlargement of the thyroid gland and occurring with a female&rcolon;male ratio of 5&rcolon;1. This article reports the analysis of an Italian three-generation pedigree MNG, including 10 affected females and 2 affected males. After linkage to candidate regions previously implicated in various forms of goiter was excluded, a novel MNG locus was searched. Because no male-to-male transmission was present in the study pedigree, an X-linked autosomal dominant pattern of inheritance was hypothesized. Therefore, 18 markers spaced at 10-cM intervals on the X chromosome were examined. A significant LOD score was observed in the Xp22 region, where marker DXS1226 generated a maximum LOD score of 4.73 at a recombination fraction of 0. Analysis of six flanking microsatellites confirmed these data, and haplotype inspection delimited a 9.6-cM interval lying between DXS1052 and DXS8039.

Premature ovarian failure

Secondary amenorrhoea with elevated gonadotrophins occurring under the age of 40 (premature ovarian failure (POF)), and at the age between 41 and 44 years (early menopause (EM)), respectively, affects 1–2% and 5% of women in the general population. Objective of this study was to evaluate the prevalence of familial cases of POF and EM and to assess the clinical and genetic characteristics of these patients. One hundred and sixty women with idiopathic secondary amenorrhoea before the age of 45 and serum follicle-stimulating hormone (FSH) levels greater than or equal to 40 IU/l were included in the study. Tests performed on patients included complete medical history, pedigree’s analysis, clinical pelvic examination, gonadotrophins and thyroid assessment, chromosomal analysis. The 160 patients included in the study showed idiopathic POF ( n=130) or EM ( n=30). Following pedigree assessment, we were able to identify an incidence of familial cases of 28.5% in the POF group ( n=37) and of 50% in the EM group ( n=15). POF and EM condition were often present in the same family. There were no differences between POF and EM patients and between familial and sporadic cases regarding age at menarche, personal history, gynaecological history, weight, height and diet habits. There was a statistically significant difference between sporadic and familial cases in age at POF onset: 32.0±7.3 years (12–40) compared to 35.0±5.8 (18–40), respectively ( P<0.05). The POF and EM families identified showed two or more affected females and transmission through either maternal or paternal relatives; in four families both maternal and paternal transmission was observed. This study suggests that idiopathic POF and EM conditions, differing only in age of menopause onset, may represent a variable expression of the same genetic disease. The different age of menopause onset in these patients may be explained by genetic heterogeneity and/or by different environmental factors. Our results indicate a high rate of familial transmission of the condition. Pedigree’s analysis suggests an autosomal or an X-linked dominant sex-limited pattern of inheritance for POF and EM.

Say-Meyer syndrome: A new case with magnetic resonance imaging of the brain, cardiac abnormality and X-linked dominant inheritance pattern

We report a new case of Say-Meyer syndrome, a rare X-linked disorder characterized by metopic suture synostosis, a high-arched palate, short stature and delayed development. Proband was a nine-month-old boy admitted to our hospital for evaluation of failure to thrive and global developmental delay. Genetics evaluation revealed: marked growth failure; microcephaly; a closed anterior fontanelle; hypotelorism; esotropia; long eyelashes; a high, narrow palate; distal hypospadias. Neurologic examination demonstrated diffuse hypotonia, diminished deep tendon reflexes, and excessive head lag. A search of the London Dysmorphology and POSSUM databases suggested Say-Meyer syndrome as the unifying diagnosis.This infant's medical history was complicated by prematurity at 32 weeks gestation, postnatal supplemental oxygen requirement and abnormal heart sounds. Cardiac evaluation identified Ebstein anomaly of the tricuspid valve as the etiology of his cardiac problems requiring ongoing medical surveillance.Magnetic resonance imaging (MRI) of the brain revealed a decreased volume of white matter with associated atrophy. The brain stem was small. The corpus callosum was thin and the genu and rostrum were not visualized. Increased signal intensity in the periventricular regions suggested periventricular leukomalacia. The ventricles were enlarged. Skull radiographs showed a decreased interorbital distance and a sclerotic metopic suture.X-linked recessive inheritance has been described. The infant's mother attended special education classes. She had marked hypotelorism, a long face, a high-arched palate, and a thin body habitus.This case of Say-Meyer syndrome includes the first report of brain MRI findings and a previously unreported cardiac defect. Clinical features noted in the mother of this infant that suggest that Say-Meyer syndrome may be an X-linked dominant disorder with variable penetrance rather than an X-linked recessive disorder.

PRENATAL SONOGRAPHIC FINDINGS ASSOCIATED WITH SPORADIC SUBCORTICAL NODULAR HETEROTOPIA

In Brief Background Subcortical nodular heterotopia is a neuronal migration disorder of uncertain etiology. This disorder occurs primarily in females and has a familial X-linked dominant inheritance pattern. The predominant symptom associated with heterotopia is seizures. Case At 23 weeks' gestation, prenatal sonography disclosed an isoechoic supratentorial intracranial mass causing right-sided shift of midline structures and compression of the contralateral cerebral ventricle. Serial ultrasound examinations of this mass were significant for the absence of invasion into surrounding structures, gross enlargement of cranial biometric parameters, and hydrocephalus and hydrops fetalis. Neonatal magnetic resonance imaging findings were consistent with gray matter heterotopia and were confirmed as such by brain biopsy. Conclusion Subcortical nodular heterotopia manifested unique prenatal sonographic findings. This case suggests the possibility of prenatal diagnosis in families at risk for this lesion. Prenatal ultrasonography at 23 weeks' gestation revealed subcortical nodular heterotopia that presented as an isoechoic intracranial mass displacing midline structures.

Prenatal Sonographic Findings Associated with Sporadic Subcortical Nodular Heterotopia

Background: Subcortical nodular heterotopia is a neuronal migration disorder of uncertain etiology. This disorder occurs primarily in females and has a familial X-linked dominant inheritance pattern. The predominant symptom associated with heterotopia is seizures.Case: At 23 weeks’ gestation, prenatal sonography disclosed an isoechoic supratentorial intracranial mass causing right-sided shift of midline structures and compression of the contralateral cerebral ventricle. Serial ultrasound examinations of this mass were significant for the absence of invasion into surrounding structures, gross enlargement of cranial biometric parameters, and hydrocephalus and hydrops fetalis. Neonatal magnetic resonance imaging findings were consistent with gray matter heterotopia and were confirmed as such by brain biopsy.Conclusion: Subcortical nodular heterotopia manifested unique prenatal sonographic findings. This case suggests the possibility of prenatal diagnosis in families at risk for this lesion.