RESUMEN
BACKGROUND: Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient's symptoms, opening new avenues for diagnosis and management. CASE PRESENTATION: We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). CONCLUSION: This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.
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Acondroplasia , Disostosis Mandibulofacial , Microcefalia , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Ribonucleoproteína Nuclear Pequeña U5 , Humanos , Microcefalia/genética , Microcefalia/diagnóstico , Microcefalia/complicaciones , Femenino , Disostosis Mandibulofacial/genética , Acondroplasia/genética , Acondroplasia/complicaciones , Ribonucleoproteína Nuclear Pequeña U5/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Factores de Elongación de Péptidos/genética , FenotipoRESUMEN
BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is a rare autosomal dominant disease caused by mutations in KIF11 which disrupt EG5 protein function, impacting the development and maintenance of retinal and lymphatic structures due to its expression in the retinal photoreceptor cilia. The primary ocular finding in MCLMR is chorioretinopathy. Additional features can include microphthalmia, angle-closure glaucoma, persistent hyperplastic primary vitreous, cataract, pseudo-coloboma, persistent hyaloid artery, and myopic or hypermetropic astigmatism. The appearance of the chorioretinal lesions as white to pinkish, round, non-elevated atrophic areas devoid of blood vessels resembles the lacunae in Aicardy syndrome. Due to the lack of systematic description of the lesions and significant phenotypical variability, there is an impending need for a detailed report of each case. CASE PRESENTATION: A child with microcephaly detected in the third trimester of gestation began her following in the ophthalmology department due to a non-visually significant cataract. Shortly after, she developed nystagmus and large-angle alternating esotropia with cross-fixation. Her fundus initially showed a pallid optic disc and pigmentary changes, developing thereafter retinal lacunae and a retinal fold. Her differential diagnosis accompanied the dynamic changes in her fundus, which included congenital infections, Leber´s Congenital Amaurosis and Aicardy syndrome. At 19 months old, genetic testing identified a heterozygous mutation (c.1159 C > T, p.Arg387*) in the KIF11 gene. The patient underwent bilateral medial rectus muscle recession surgery at 2 years old for persistent esotropia, with significant improvement. Refraction revealed a hyperopic astigmatism in both eyes (+ 0.25 -2.50 × 180 OD and + 0.75 -2.00 × 170 OS). She continues to require right eye patching for 2 hours daily. CONCLUSIONS: This case report expands the phenotypic spectrum of MCLMR by demonstrating a unique combination of retinal features which sheds new light on differential diagnosis from Aicardy syndrome. Our findings emphasize the significant phenotypic variability associated with MCLMR, particularly regarding ocular involvement. This underscores the importance of detailed clinical evaluation and comprehensive reporting of cases to improve our understanding of the disease spectrum and genotype-phenotype correlations.
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Discapacidad Intelectual , Linfedema , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/diagnóstico , Femenino , Linfedema/genética , Linfedema/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Displasia Retiniana , Cinesinas , FaciesRESUMEN
BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare genetic condition resulting in multiple congenital anomalies, including facial dysmorphism, structural anomalies of the internal organs, functional disorders, and, although less commonly, ocular abnormalities. To present a child with MWS and eye abnormalities. METHODS: A 3-year-old boy was born at 37 weeks of pregnancy with dysmorphic features, neurodevelopmental disorders, genetically confirmed MWS, nystagmus, strabismus, and suspicion of congenital glaucoma. Ophthalmic examination was carried out under general anesthesia; eyeball ultrasound and electrophysiological examination (flash visual evoked potentials) were also performed. RESULTS: The examinations revealed nystagmus, a normal response of pupils to light in both eyes, and normal intraocular pressure, that is, 17 and 18â mmâ Hg in the right and left eye, respectively. Corneal thickness was 606 µm in the right eye and 588 µm in the left eye. Gonioscopy revealed displacement of Schwalbe line anterior to the limbus of the cornea (posterior embryotoxon). Fundus examination revealed a pink optic disk with a cup-to-disc ratio of 0.5, macular pigment regrouping, and normal blood vessels. Flash visual evoked potentials: P2 latency was normal. P2 amplitude from the left hemisphere was reduced to 50%, and P2 amplitude over the right hemisphere was normal. CONCLUSION: Children with genetically determined congenital anomalies need regular ophthalmic checkups to accurately assess the eye and determine the prospects of vision function development.
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Enfermedad de Hirschsprung , Discapacidad Intelectual , Microcefalia , Humanos , Masculino , Preescolar , Microcefalia/genética , Microcefalia/diagnóstico , Discapacidad Intelectual/genética , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/fisiopatología , Facies , Potenciales Evocados Visuales/fisiología , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/fisiopatologíaRESUMEN
INTRODUCTION: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a multifaceted etiology. This case report explores the ischemic cryptogenic vascular dissection as a potential underlying cause of ASD. METHODS: A 9-year-old child presented with symptoms of ASD, including social interaction difficulties, repetitive behaviors, and cognitive challenges. Despite conventional ASD treatments, significant improvement was only observed after addressing an underlying ischemic cryptogenic vascular dissection identified through DCE-CT. RESULTS: Following a reconstructive treatment approach to the vascular dissection, the patient showed marked improvement in cognitive functions, social abilities, and a reduction in ASD-related symptoms whether during the perioperative period or during approximately 5-month follow-up. CONCLUSION: This case suggests that ischemic cryptogenic vascular dissection may contribute to the symptoms of ASD. Identifying and treating underlying vascular anomalies may offer a new avenue for mitigating ASD symptoms, emphasizing the need for comprehensive diagnostic estimations in ASD management.
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Trastorno del Espectro Autista , Humanos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/complicaciones , Niño , Masculino , Microcefalia/complicaciones , Microcefalia/diagnósticoRESUMEN
We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy. Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion. Whole-exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val). The neurodevelopmental disorder associated with the ARF3 gene is exceptionally rare, with only two previously documented cases in the literature. This disorder is characterized by global developmental delay and brain malformations, particularly affecting the white matter, cerebellum, and brainstem. It can also manifest as acquired microcephaly and epilepsy. These phenotypic characteristics align with Golgipathies, underscoring the significance of considering this group of conditions in relevant clinical contexts. In cases where a Z-shaped morphology of the brainstem is observed, ARF3-associated disorder should be included in the list of differential diagnoses.
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Factores de Ribosilacion-ADP , Trastornos del Neurodesarrollo , Femenino , Humanos , Factores de Ribosilacion-ADP/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Imagen por Resonancia Magnética , Microcefalia/genética , Microcefalia/patología , Microcefalia/diagnóstico , Mutación/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Trastornos del Neurodesarrollo/diagnóstico por imagen , Fenotipo , Sustancia Blanca/patología , Sustancia Blanca/diagnóstico por imagen , PreescolarAsunto(s)
Cinesinas , Microcefalia , Enfermedades de la Retina , Humanos , Microcefalia/diagnóstico , Microcefalia/genética , Microcefalia/complicaciones , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Enfermedades de la Retina/etiología , Cinesinas/genética , Masculino , Femenino , Tomografía de Coherencia Óptica , Mutación , Retina/patología , Retina/diagnóstico por imagenAsunto(s)
Distonía , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/complicaciones , Microcefalia/diagnóstico , Distonía/diagnóstico , Corea/genética , Corea/diagnóstico , Corea/complicaciones , Facies , Masculino , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/complicaciones , Femenino , Atetosis/genética , Atetosis/diagnóstico , Atetosis/etiologíaRESUMEN
INTRODUCTION: Microcephaly, characterized by abnormal head growth, can often serve as an initial indicator of congenital, genetic, or acquired disorders. In this study, we sought to evaluate the effectiveness of chromosomal microarray (CMA) testing in detecting abnormalities in both prenatal and postnatal cases of microcephaly. MATERIALS AND METHODS: CMA Testing: We conducted CMA testing on 87 prenatally-detected microcephaly cases and 742 postnatal cases at a single laboratory. We evaluated the CMA yield in relation to specific clinical characteristics. RESULTS: In prenatal cases, pathogenic and likely pathogenic (LP) results were identified in 4.6% of cases, a significantly higher rate compared to low-risk pregnancies. The male-to-female ratio in this cohort was 3, and the CMA yield was not influenced by gender or other clinical parameters. For postnatal cases, the CMA yield was 15.0%, with a significantly higher detection rate associated with dysmorphism, hypotonia, epilepsy, congenital heart malformations (CHM), learning disabilities (LD), and a history of Fetal growth restriction (FGR). No specific recurrent copy number variations (CNVs) were observed, and the rate of variants of unknown significance was 3.9%. CONCLUSIONS: The yield of CMA testing in prenatal microcephaly is lower than in postnatal cases (4.6% vs. 15%). The presence of microcephaly, combined with dysmorphism, hypotonia, epilepsy, CHD, LD, and FGR, significantly increases the likelihood of an abnormal CMA result.
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Análisis por Micromatrices , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/diagnóstico , Femenino , Embarazo , Masculino , Diagnóstico Prenatal/métodos , Recién Nacido , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/diagnóstico , Variaciones en el Número de Copia de ADN , Adulto , Aberraciones Cromosómicas , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/diagnóstico , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/diagnóstico , Epilepsia/genética , Epilepsia/diagnóstico , Hipotonía Muscular/genética , Hipotonía Muscular/diagnósticoRESUMEN
BACKGROUND: Phosphoserine aminotransferase deficiency (PSATD) is an autosomal recessive disorder associated with hypertonia, psychomotor retardation, and acquired microcephaly. Patients with PSATD have low concentrations of serine in plasma and cerebrospinal fluid. METHODS: We reported a 2-year-old female child with developmental delay, dyskinesia, and microcephaly. LC-MS/MS was used to detect amino acid concentration in the blood and whole-exome sequencing (WES) was used to identify the variants. PolyPhen-2 web server and PyMol were used to predict the pathogenicity and changes in the 3D model molecular structure of protein caused by variants. RESULTS: WES demonstrated compound heterozygous variants in PSAT1, which is associated with PSATD, with a paternal likely pathogenic variant (c.235G>A, Gly79Arg) and a maternal likely pathogenic variant (c.43G>C, Ala15Pro). Reduced serine concentration in LC-MS/MS further confirmed the diagnosis of PSATD in this patient. CONCLUSIONS: Our findings demonstrate the importance of WES combined with LC-MS/MS reanalysis in the diagnosis of genetic diseases and expand the PSAT1 variant spectrum in PSATD. Moreover, we summarize all the cases caused by PSAT1 variants in the literature. This case provides a vital reference for the diagnosis of future cases.
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Microcefalia , Trastornos Psicomotores , Convulsiones , Transaminasas , Preescolar , Femenino , Humanos , Cromatografía Liquida , Secuenciación del Exoma , Cromatografía Líquida con Espectrometría de Masas , Microcefalia/genética , Microcefalia/diagnóstico , Serina/genética , Espectrometría de Masas en Tándem , Transaminasas/deficienciaRESUMEN
BACKGROUND: The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures. METHOD: Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server. RESULTS: The proband is an 11-year-old Iranian-Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10-20th days of life, when refractory epileptic gaze and unilateral tonic-clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients. CONCLUSION: In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian-Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients.
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Encefalopatías , Discapacidad Intelectual , Microcefalia , Malformaciones del Sistema Nervioso , Femenino , Humanos , Niño , Microcefalia/genética , Microcefalia/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Irán , Encefalopatías/genética , AtrofiaRESUMEN
BACKGROUND: Cohen syndrome (CS) is a rare autosomal recessive inherited condition characterized by pathological changes affecting multiple systems. The extensive clinical variability associated with CS poses a significant diagnostic challenge. Additionally, there is limited documentation on the co-occurrence of CS with psychiatric symptoms. CASE REPORT: We report a case of a 30-year-old patient exhibiting characteristic physical features and psychiatric symptoms. Whole exome sequencing identified two heterozygous variants, a nonsense variation c.4336 C > T and a missense mutation c.4729G > A. Integrating clinical manifestations with genetic test results, we established the diagnosis of CS combined with psychiatric symptoms. CONCLUSIONS: This case introduces a novel missense variant as a candidate in the expanding array of VPS13B pathogenic variants. Its clinical significance remains unknown, and further investigation may broaden the spectrum of pathogenic variants associated with the VPS13B gene. Early diagnosis of CS is crucial for the prognosis of young children and holds significant importance for their families.
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Dedos/anomalías , Discapacidad Intelectual , Microcefalia , Hipotonía Muscular , Miopía , Obesidad , Degeneración Retiniana , Niño , Humanos , Preescolar , Adulto , Microcefalia/diagnóstico , Microcefalia/genética , Documentación , Discapacidades del DesarrolloRESUMEN
Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.
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Metilación de ADN , Facies , Enfermedad de Hirschsprung , Proteínas de Homeodominio , Discapacidad Intelectual , Microcefalia , Proteínas Represoras , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Microcefalia/genética , Microcefalia/diagnóstico , Microcefalia/patología , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/patología , Proteínas de Homeodominio/genética , Proteínas Represoras/genética , Femenino , Masculino , Niño , Preescolar , Adolescente , Islas de CpGRESUMEN
Ocular associations in Mowat-Wilson syndrome (MWS) are rare. Those involving the anterior segment are scarce in the literature. We describe a child with genetic confirmation of MWS that presented with acquired onset of unilateral anterior iris adhesions with no known trauma.
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Enfermedad de Hirschsprung , Discapacidad Intelectual , Enfermedades del Iris , Microcefalia , Niño , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Facies , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/genética , Microcefalia/complicaciones , Microcefalia/diagnóstico , Microcefalia/genética , Enfermedades del Iris/diagnóstico , Adherencias Tisulares , IrisRESUMEN
DYRK1A Syndrome (OMIM #614104) is caused by pathogenic variations in the DYRK1A gene located on 21q22. Haploinsufficiency of DYRK1A causes a syndrome with global psychomotor delay and intellectual disability. Low birth weight, growth restriction with feeding difficulties, stature insufficiency, and microcephaly are frequently reported. This study aims to create specific growth charts for individuals with DYRK1A Syndrome and identify parameters for size prognosis. Growth parameters were obtained for 92 individuals with DYRK1A Syndrome (49 males vs. 43 females). The data were obtained from pediatric records, parent reporting, and scientific literature. Growth charts for height, weight, body mass index (BMI), and occipitofrontal circumference (OFC) were generated using generalized additive models through R package gamlss. The growth curves include height, weight, and OFC measurements for patients aged 0-5 years. In accordance with the literature, the charts show that individuals are more likely to present intrauterine growth restriction with low birth weight and microcephaly. The growth is then characterized by severe microcephaly, low weight, and short stature. This study proposes growth charts for widespread use in the management of patients with DYRK1A syndrome.
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Discapacidad Intelectual , Microcefalia , Masculino , Femenino , Niño , Humanos , Microcefalia/diagnóstico , Microcefalia/genética , Gráficos de Crecimiento , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Síndrome , Índice de Masa Corporal , Estatura/genéticaRESUMEN
ATP1A2 encodes a subunit of sodium/potassium-transporting adenosine triphosphatase (Na+ /K+ -ATPase). Heterozygous pathogenic variants of ATP1A2 cause familial hemiplegic migraine, alternating hemiplegia of childhood, and developmental and epileptic encephalopathy. Biallelic loss-of-function variants in ATP1A2 lead to fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, resulting in fetal death. Here, we describe a patient with compound heterozygous ATP1A2 variants consisting of missense and nonsense variants. He survived after birth with brain malformations and the fetal akinesia/hypokinesia sequence. We report a novel type of compound heterozygous variant that might extend the disease spectrum of ATP1A2.
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Microcefalia , Migraña con Aura , Masculino , Humanos , Hipocinesia , ATPasa Intercambiadora de Sodio-Potasio/genética , Microcefalia/diagnóstico , Microcefalia/genética , Hemiplejía , SíndromeRESUMEN
INTRODUCTION: Intrauterine microcephaly is a complex and lifelong condition that poses significant ethical challenges for clinicians and parents. The prognosis of microcephaly is highly variable and depends on the underlying cause and severity. In addition, microcephaly is often associated with various comorbidities, including intellectual disability, developmental delay, and epilepsy. Ultrasonography (US) is currently the most commonly used imaging modality for detecting microcephaly in the second trimester of pregnancy. However, antenatal brain magnetic resonance imaging (MRI) is increasingly being used as a more sensitive tool to identify structural abnormalities that may suggest a specific diagnosis. In this study, we report a case series of microcephaly diagnosed through the combination of MRI and US. PATIENT CONCERNS: How to utilize a combination of MRI and US to screen for fetal microcephaly. DIAGNOSIS: Based on the results of US and MRI examinations, patient 1 was found to have other craniocerebral malformations, patient 2 demonstrated macrogyria, and patient 3 exhibited skull irregularities. INTERVENTIONS: The pregnancies of all 3 patients were terminated through the induction of labor by injecting Rivanol into the amniotic cavity. OUTCOMES: The 3 patients were discharged after a period of observation. CONCLUSION: US is an important tool for diagnosing fetal microcephaly. However, MRI can overcome the limitations of US and detect additional brain structural abnormalities, thereby providing more specific and valuable prenatal diagnostic information. Therefore, combining MRI and US has significant diagnostic value for fetal microcephaly.