ABSTRACT Children with cleft palate often experience delays in early language development, with verbal abilities tending to lag behind nonverbal abilities. However, the relationship between early speech and language intervention (EI) and specific domains of intelligence remains unclear. This retrospective observational study examined whether participation in an EI program was associated with crystallized and fluid intelligence at 4 and 6 years of age. Clinical records of children who underwent palatoplasty between 2010 and 2023 were reviewed. At age 4, 38 children in the EI group and 40 controls completed the Wechsler Preschool and Primary Scale of Intelligence, while at age 6, 23 children in the EI group and 15 controls completed the Wechsler Intelligence Scale for Children–Fourth Edition. The age‐4 and age‐6 samples did not necessarily include the same participants. Verbal indices were used as measures of crystallized intelligence and nonverbal indices as measures of fluid intelligence. Group differences were analyzed using adjusted multiple linear regression models controlling for sex and cleft type. At age 4, EI participation was significantly associated with higher Verbal IQ and, after adjustment, higher Full‐Scale IQ. At age 6, the EI group showed significantly higher Full‐Scale IQ and Verbal Comprehension Index, with these associations remaining significant after adjustment. No significant associations were found for nonverbal indices. These findings suggest that structured early speech and language intervention may enhance verbal and crystallized intelligence in children with cleft palate.
Low-flow vascular malformations (LFVMs) are congenital vascular anomalies with heterogeneous clinical behavior and variable treatment response. This retrospective study described the clinical characteristics, treatment patterns, and modality-specific outcomes of children aged 0-18 years with LFVM evaluated at Hacettepe University between January 1999 and June 2020. Lesions were classified as capillary, venous, lymphatic, or combined LFVMs, and demographic, clinical, imaging, treatment, follow-up, and adverse event data were reviewed. Radiologic/clinical and symptomatic responses were assessed for sirolimus, image-guided sclerotherapy, and surgery. Among the patients, lesions were combined in 94 (40.5%), lymphatic in 80 (34.5%), and venous in 58 (25.0%). The mean age at diagnosis was 54.6 ± 55.2 months, the mean diagnostic delay was 37.6 ± 48.1 months, and the head and neck was the most frequent primary location (44.4%). Mean follow-up was 50.1 ± 42.3 months. Sirolimus was administered to 118 patients and achieved radiologic/clinical response in 55.1% and symptomatic improvement in 75.4%, with the highest symptomatic improvement observed in lymphatic malformations (84.2%). After sirolimus discontinuation, 19 patients experienced radiologic/clinical progression or symptom worsening. Sclerotherapy (n = 74) achieved radiologic/clinical and symptomatic response rates of 67.6% and 79.7%, respectively, whereas surgery (n = 54) achieved rates of 79.6% and 61.1%, respectively. Progressive disease at the last follow-up was rare (1.3%). Overall, multimodal therapy provided substantial disease control in this long-term pediatric LFVM cohort. Sirolimus primarily improved symptoms, particularly in lymphatic and combined lesions, while sclerotherapy and surgery were effective when selected according to lesion phenotype and treatment goals.
In Ethiopia, cleft lip and/or palate is a major public health concern. In this study, we compiled clinical statistics on patients who presented during 7 years of surgical medical aid missions and examined possible background factors underlying the striking imbalance in cleft types (i.e., the apparent absence of isolated cleft palate) compared with those in developed countries. All 150 patients examined during surgical medical aid missions conducted between 2013 and 2019 were included. Age, sex, cleft type, surgery performed, and reasons for cancellation were analyzed retrospectively. The mean age of the 150 patients was 4.9 years. Most cases were cleft lip (unilateral cleft lip with or without cleft alveolus) and cleft lip and palate, whereas only two cases (1.3%) were isolated cleft palate. Surgery was performed in 93 cases (62.0%); however, all procedures were cheiloplasty, and palatoplasty was not performed for safety-related reasons. The surgical cancellation rate was high (38.0%), mainly due to infection and malnutrition. The extreme paucity of patients with isolated cleft palate suggests an "unobserved mortality" in the region. Early death (natural selection) due to feeding difficulties and lack of disease recognition may be the contributing factors. This "cleft-type imbalance" indicates an urgent need not only to provide surgery, but also to implement early screening and nutritional interventions at the community level.
The Mammalian Phenotype Ontology is a comprehensive controlled vocabulary encompassing phenotypic terms related to congenital anomalies, developmental abnormalities, and other mammalian phenotypes, developed by Mouse Genome Informatics. Although this ontology was originally created in English, multilingualization is essential for broadening its impact by improving accessibility for researchers worldwide. To address this need, we developed a Japanese translation of the Mammalian Phenotype Ontology to support non-English-speaking research communities in Japan. The Japanese translation of this ontology was produced using a systematic human-in-the-loop workflow consisting of machine translation, systematic manual review, and expert curation. Manual curation is a critical component of this process, as automated translation alone is insufficient for accurately rendering domain-specific phenotype terminology. The Japanese-translated Mammalian Phenotype Ontology has been integrated into multiple data resources and search platforms, including experimental animal resource databases and disease-oriented data integration services. This integration enables users to search for and interpret annotated mouse phenotypes using Japanese terminology and has significantly improved the accessibility and usability of Mammalian Phenotype Ontology-based services for non-English-speaking Japanese researchers, students, and laboratory animal caretakers. In addition, the Japanese translation of the Mammalian Phenotype Ontology is publicly released and formally incorporated into the official Mammalian Phenotype Ontology distribution through collaboration with Mouse Genome Informatics, allowing regular updates synchronized with ongoing development. This study highlights the importance of localizing ontology vocabularies to advance global accessibility and presents a practical framework for systematic ontology translation.
X-rays are a form of ionizing radiation that has sufficient energy to remove electrons from atoms, thereby creating potentially harmful ions. X-ray irradiation during organogenesis can have profound detrimental effects, depending on the developmental stage and irradiating energy. In this study, we examined the impact of X-ray irradiation on zebrafish development at 36 h post-fertilization and observed marked jaw malformation, which was alleviated by folic acid pretreatment. Mechanistic studies revealed that folic acid pretreatment suppressed irradiation-induced production of reactive oxygen species. Transcriptome analysis performed at 24 and 48 h post-irradiation revealed dysregulated expression of apolipoprotein A-IV a (apoa4a), methionine adenosyltransferase 1A (mat1a), heat shock protein 90 alpha class A member 1 tandem duplicate 1 (hsp90aa1.1), FKBP prolyl isomerase 5 (fkbp5), plac8 onzin related protein 3 (ponzr3), and prostaglandin E synthase 3a (ptges3a), which was not observed in zebrafish treated with folic acid before the irradiation. These findings suggest that folic acid alleviates X-ray irradiation-induced jaw malformation in zebrafish, at least in part, by reducing oxidative stress and ameliorating dysregulated gene expression.
Rubinstein-Taybi syndrome (RTS) is caused by germline loss-of-function variants of CREBBP or EP300, which function as histone acetyltransferases and act as tumor suppressors. Various benign or malignant tumors have been reported in RTS, suggesting tumor predisposition. To date, five patients with RTS complicated by neuroblastoma have been reported, and pathogenic germline variants were confirmed in two of the patients. We report a 2-year-old male with neuroblastoma and RTS harboring a germline CREBBP missense variant at the histone acetyltransferase (HAT) domain. Neuroblastoma was diagnosed at 4 months of age, and histological evaluation classified the tumor as low risk. The neuroblastoma was stable at 2 years of age. His dysmorphic features and developmental delay were consistent with phenotypes of RTS. Whole genome sequencing of both tumor and germline identified a de novo missense variant of CREBBP (NM_004380.3:c.4862T>A p.(Leu1621Gln)). No other contributing germline or somatic variants were identified, except for polyploidy involving chromosomes 7, 12, and 17. Our results suggest that germline loss-of-function of CREBBP may contribute to tumor predisposition factor since somatic variants of CREBBP and EP300 have been identified in neuroblastoma. Paired tumor-normal genome sequencing enabled comprehensive analysis of germline tumor predisposition, as well as genomic profiles of tumor tissue.
Consanguineous marriage is common in Pakistan and has been linked to an elevated risk of congenital anomalies (CAs), yet community-based evidence from rural settings remains limited. This study examined the prevalence and patterns of congenital anomalies and assessed their association with consanguinity in a rural population of Punjab, Pakistan. A cross-sectional survey was conducted among 300 married couples in Union Council Kamrial, District Attock. Information on socio-demographic characteristics, reproductive history, and congenital anomalies was collected using a structured questionnaire and, where possible, verified through clinical records. Data were analyzed using descriptive and bivariate statistical methods. Consanguineous unions were reported by 77.7% (n = 233) of couples, with first-cousin marriages comprising 63.9% of these cases. Overall, 18.0% (n = 54) of couples reported at least one child with a congenital anomaly. Although the prevalence was higher among consanguineous couples (18.9%) than non-consanguineous couples (14.9%), this difference was not statistically significant (p = 0.457). A prior history of congenital anomalies showed a strong association with recurrence, reported by 92.3% of affected couples (p < 0.0001). Higher prevalence was also observed among older couples and those with lower levels of partner education. These findings suggest that, within this rural context, factors such as familial history, parental age, and socio-demographic conditions may be more influential than consanguinity alone in shaping the risk of congenital anomalies. The results underscore the need for targeted genetic counseling, improved health literacy, and strengthened maternal and child health services in underserved communities.
The phosphatidylinositol-3-kinase (PI3K)-AKT-mTOR pathway plays a central role in cellular growth and survival, and somatic activating variants in PIK3CA cause PIK3CA-related overgrowth spectrum (PROS). Because these variants arise postzygotically, affected individuals exhibit somatic mosaicism, making molecular diagnosis challenging, particularly when only peripheral blood is available. We report an infant with PROS presenting with hemimegalencephaly, facial infiltrating lipomatosis, epidermal nevi, and unilateral woolly hair. A hotspot PIK3CA variant (c.1633G>A, p.Glu545Lys) was identified in the resected brain tissue but not in the peripheral blood. Notably, the variant was detected in DNA extracted from hair follicles of curly hair on the affected side of the scalp, whereas it was absent in follicles from straight hair on the contralateral side. Droplet digital PCR demonstrated variant allele fractions of 24.7%-27.6% in brain tissue and 32.3% in curly hair. These findings highlight the utility of hair follicles as a minimally invasive and accessible source of DNA for detecting somatic mosaic variants in PROS. The spatial concordance between genotype and hair phenotype suggests a possible association between PIK3CA mosaicism and localized hair abnormalities, although causality remains to be established.
Previous histological studies have shown that the extraocular muscles (EOMs) within the orbit are unique among skeletal muscles in both developmental origin and timing. However, three-dimensional (3D) morphological information and quantitative growth data remain limited. This study aimed to reconstruct 3D images of the EOMs during the human embryonic and early fetal periods (crown-rump length, 20-86 mm) using magnetic resonance imaging (MRI) data and quantify their growth. In specimens from the late embryonic period, all six EOMs controlling eye movement were recognizable on MRI and could be segmented for morphological analysis. The five EOMs originating from the common tendinous ring appeared to become closer as they widened during growth. Overall, the basic morphology of each EOM was broadly maintained from the late embryonic to early fetal period, with the most prominent change observed in the superior oblique muscle (SOM), whose bending angle at the trochlea changed from nearly rectangular at the end of the embryonic period to acute during the early fetal period. The lateral rectus muscle showed the largest volume and mean cross-sectional area among the EOMs in the early fetal period. Mean cross-sectional area increased at a similar rate among the four rectus muscles, but less in the inferior oblique muscle and much less in the SOM. Growth of each EOM strongly correlated with eyeball growth. These findings suggest that the four rectus muscles grow in a coordinated manner, whereas the oblique muscles follow distinct growth patterns during early orbital development.
The HDAC8 variant is causative for X-linked Cornelia de Lange syndrome (CdLS) and shows skewed X-inactivation in heterozygous female patients, who tend to present with milder phenotypes than hemizygous male patients. We report a slightly deep intronic HDAC8 variant, NM_018486.3:c.112-15C>A, in a family with CdLS. Patient 1 (male) had a hemizygous HDAC8 variant, showed a severe CdLS phenotype including profound developmental delay and multiple congenital abnormalities, and was deceased at 7 years old. Patient 2 (female) was a younger sister of Patient 1 and revealed mild developmental delay and consistent dysmorphic features with CdLS. Patient 2 and their mother (Patient 3) had heterozygous variants and showed a skewed X-inactivation pattern. cDNA deep sequencing of peripheral blood indicated aberrantly spliced transcripts in 0.53% of sequence reads in Patient 2, but not in Patient 3. This aberrant splicing likely results in nonsense-mediated mRNA decay with loss-of-function effects. In Patient 3, the mutated allele was strongly inactivated, and normal transcripts from the reference allele were predominant. cDNA deep sequencing was required to evaluate the pathogenicity of the intronic variants. This report suggests that leaky splicing, as well as X-inactivation, may contribute to the variation in familial phenotypic severity of HDAC8-related CdLS.
SET-related neurodevelopmental disorder (OMIM #618106) is an emerging condition for which the phenotypic spectrum remains incompletely defined. We report two unrelated Japanese individuals with distinct genomic alterations affecting SET: a de novo frameshift variant and a heterozygous 9q34.11 microdeletion encompassing the gene. Both individuals presented with global developmental delay, intellectual disability, and overlapping craniofacial features, including a broad nasal bridge, broad nasal tip, wide mouth, and periorbital fullness. These features were broadly consistent with those described in previously reported individuals, suggesting a shared pattern of craniofacial characteristics associated with SET disruption. Both individuals exhibited a sociable behavioral tendency was observed in both individuals, whereas formal neurodevelopmental diagnoses such as autism spectrum disorder or attention-deficit/hyperactivity disorder were not consistently identified. Comparison with previously reported individuals, including those with protein-truncating variants, missense variants, and copy number alterations, showed that neurodevelopmental impairment is a consistent feature, while craniofacial and behavioral findings appear variable. In the individual with the microdeletion, contributions from neighboring genes cannot be fully excluded. These findings further delineate the clinical spectrum of SET-related neurodevelopmental disorder and support the importance of careful phenotypic characterization in its recognition.
Craniofacial development requires precise coordination of epithelial patterning and morphogenesis. However, the molecular mechanisms governing olfactory epithelium development remain incompletely understood. Retinoic acid (RA) signaling and Gata3 have each been independently implicated in craniofacial morphogenesis, particularly in the formation of the primitive choanae, which constitute the opening between the nasal cavity and the oral cavity. Here, we generated a tamoxifen-inducible, genetically controlled compound mutant mouse model to simultaneously disrupt Rdh10, a rate-limiting enzyme for RA signaling, and Gata3 during early craniofacial development. We show that while deletion of Rdh10 following tamoxifen administration at E8.5 does not result in obvious craniofacial abnormalities, combined loss of Rdh10 and Gata3 leads to fully penetrant bilateral choanal atresia and severe defects in olfactory epithelium morphogenesis. Immunohistochemical analyses revealed a marked reduction in PAX6 and SIX1 positive cells and a concomitant expansion of SOX2 positive cells in compound mutant embryos. These results demonstrate that RA-Gata3 signaling cooperatively regulates olfactory epithelium development by controlling the balance between progenitor maintenance and lineage specification. We propose that the RA-Gata3 signaling pathway orchestrates a transcriptional network involving Pax6, Six1, and Sox2 to ensure proper epithelial patterning, branching morphogenesis, and choanae formation during early craniofacial development.
Geleophysic dysplasia type 1 is a rare skeletal dysplasia caused by biallelic pathogenic variants in ADAMTSL2. Affected children typically show a "happy-natured facial appearance," postnatal short stature with acromelic limb shortening, progressive joint contracture, and skin tightness. Most patients are diagnosed in childhood, and very little is known about the neonatal manifestation. We report a Japanese girl with Geleophysic dysplasia type 1, whose neonatal manifestations were enough to raise suspicion of the disorder on retrospective clinical and radiological review. At birth, she presented with joint contractures, short digits, mild pulmonary stenosis, and a normal facial appearance, and later developed severe short stature, camptodactyly, gait disturbance, and a round face with a flat nasal bridge and upslanting palpebral fissures. The clinical constellation led to a suspicion of Geleophysic dysplasia type 1 at age 3 years, and exome sequencing revealed variants in ADAMTSL2, a recurrent pathogenic missense variant (p.Ser635Leu) and a novel nonsense variant (p.Cys666*). On radiological grounds, she manifested with the same skeletal alterations in the neonatal period and at age 3 years, including severe brachydactyly with cone-shaped epiphyses and metaphyseal broadening. The distinctive skeletal phenotype overlapped with that of Al-Gazali skeletal dysplasia, an ADAMTSL2-associated potentially lethal skeletal dysplasia, suggesting a phenotypic continuum between both entities. The present case suggests that a subset of Geleophysic dysplasia type 1 may present with diagnostic physical and radiological manifestations in the neonatal period. Early recognition of neonatal skeletal features can facilitate prompt diagnosis and early clinical management for affected children.
Medication safety must be carefully considered during pregnancy because of the potential risks to the fetus. Allergic diseases during pregnancy, oral second-generation antihistamines, such as fexofenadine and olopatadine, are often used when topical agents are insufficiently effective. However, there are limited data on their teratogenic risk, particularly in the Japanese population. A cohort study was conducted using data from Japanese teratogenicity information services at two institutions: Toranomon Hospital and the National Center for Child Health and Development. Outcomes in pregnant women exposed to fexofenadine or olopatadine during the first trimester were compared with those in controls exposed to nonteratogenic drugs. The primary endpoint was the incidence of major birth defects defined by the EUROCAT criteria. Secondary outcomes included preterm birth and low birth weight. Logistic regression analyses were performed with adjustment for maternal age, alcohol consumption, smoking, and comorbidities. In total, 1473 eligible pregnancies for the analysis of major birth defects were included. Major birth defects occurred in 1.8% of the fexofenadine group (n = 231) and 3.0% of the olopatadine group (n = 186), showing no significant increase compared with 1.8% of the control group (n = 1056). Logistic regression showed no association between either antihistamine and major birth defects, preterm birth, or low birth weight after adjustment. No consistent pattern of anomalies was identified. This study found no evidence that exposure to fexofenadine or olopatadine in the first trimester increases the risk of major birth defects. These second-generation antihistamines appear to be relatively safe in pregnant women with allergic conditions.
Distal deletion 14q syndrome is a rare chromosomal disorder characterized by variable features, including growth restriction, craniofacial dysmorphism, developmental delay, and congenital anomalies. Diagnosis is often delayed because conventional G-banding may appear normal. Neonatal recognition is rarely reported, and early phenotypic features remain insufficiently defined. We report the case of a male infant born at 37 + 6 weeks of gestation with intrauterine growth restriction, micrognathia, feeding difficulties, hypotonia, and cardiopulmonary instability. Prenatal echocardiography suggested coarctation of the aorta, while postnatal imaging revealed mild bilateral pulmonary artery branch narrowing and distal aortic arch tapering without hemodynamic significance. Research-based trio exome sequencing suggested an approximately 6.5 Mb terminal deletion of chromosome 14q32.2-q32.33, which was subsequently confirmed by chromosomal microarray. Although craniofacial features appeared subtle at birth, a retrospective review following genetic confirmation revealed additional dysmorphic traits. This case underscores the diagnostic utility of genomic testing, which enabled confirmation of distal 14q deletion at 1 month of age. In contrast, previously reported cases were typically diagnosed later in childhood. Our findings refine the neonatal phenotypic spectrum of distal deletion 14q syndrome by documenting subtle but identifiable early craniofacial, vascular, feeding, and auditory features that may prompt earlier suspicion. Early confirmation provided reassurance regarding recurrence risk and allowed for timely planning of nutritional, developmental, and audiological support. This case illustrates how genomic testing can narrow a long-standing diagnostic gap and highlights key neonatal clues that may facilitate earlier recognition of distal deletion 14q syndrome.
Omphalocele, Cloacal Exstrophy, Imperforate Anus, Spinal Defects (OEIS) complex is an extremely rare congenital disorder, and data on long-term functional and developmental outcomes remain scarce. We aimed to evaluate ambulatory, urological, and intellectual outcomes in a cohort of patients with OEIS complex. We retrospectively reviewed 10 patients with OEIS complex born at our institution between 1991 and 2021. Spinal defects were classified radiologically or intraoperatively. Ambulatory and urinary outcomes were assessed at the most recent follow-up, and intellectual status was evaluated in patients who were aged ≥ 6 years. At a mean follow-up of 114 months (range, 4-348), five patients were independently ambulatory, two were ambulatory with orthoses, and two were nonambulatory. Two patients achieved dry time with clean intermittent catheterization, while seven remained incontinent. Among seven school-aged patients, five attended regular schools, one required special education, and one could not attend due to complications. Spinal anomalies included spinal lipomas (n = 6) and terminal myelocystoceles (n = 4). In this cohort, long-term ambulatory and intellectual outcomes were generally favorable in the absence of severe complications, whereas urinary continence remained challenging. Given the rarity of OEIS complex, additional multi-institutional and multidisciplinary studies with extended follow-up are needed.
Anorectal malformation is an important congenital anomaly. Rectoperineal fistula (RPF) is one of the clinical types that fall in the rare/regional variants of the Krickenbeck classification. There is limited literature on this rare clinical type. This paper deals with its clinical presentation and the management protocol adopted by us. All patients of RPF were included. The patients were evaluated for age at presentation, the clinical presentation of the RPF, associated anomalies, and complications. After the diagnosis, all patients underwent three-stage surgery: diverting loop colostomy, posterosagittal anorectoplasty, and colostomy closure. During the study period of 10 years, we managed seven patients with RPF. The mean age of the patients at the time of first surgery and posterosagittal anorectoplasty was 2.71 days and 2.39 years, respectively. Four patients had puckered and pulled-up skin at the fistula. 2D ECHO was normal in all the patients. Ultrasound abdomen revealed an ectopic kidney and mild hydronephrosis in one patient each. The mean duration of follow-up was 3 years. All seven patients had completed all three stages of surgery. All of them have no soiling. Three patients had Grade 2 constipation. With treatment, they showed improvement, and they are in Grade 1 constipation. RPF is an uncommon variant of anorectal malformation. Any patient with a perineal fistula should be carefully examined to rule out RPF. If diagnosed, the management should be as per the rectourethral fistula. Overall outcome appears to be good.
We report a case in which a girl diagnosed with HNRNPU-associated neurodevelopmental disorder presented with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and generalized hypotonia accompanied by chorea-like involuntary movements. On the first day of hospitalization, she presented with fever and generalized clonic seizures. Twenty four hours later, she continued to experience impaired consciousness and generalized hypotonia. Her consciousness improved gradually, but chorea-like involuntary movements of the limbs were observed. From the seventh day of hospitalization, the patient repeatedly experienced difficulty in making eye contact for 20-30 s for 2-3 days. Brain MRI with diffusion-weighted imaging revealed hyperintensity from the bilateral frontal cortex to subcortical white matter and the bilateral caudate nuclei. This patient presented with chorea-like involuntary movements and generalized hypotonia, and was unable to perform antigravity movements. HNRNPU-related neurodevelopmental disorders often present with congenital hypotonia. When affected children develop acute encephalopathy associated with basal ganglia lesions, the synergistic effect of these conditions may exacerbate the hypotonia.
