Prenatal alcohol exposure and associations with physical size, dysmorphology and neurodevelopment: a systematic review and meta-analysis.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a significant public health concern, yet there is no internationally agreed set of diagnostic criteria or summary of underlying evidence to inform diagnostic decision-making. This systematic review assesses associations of prenatal alcohol exposure (PAE) and outcomes of diagnostic assessments, providing an evidence base for the improvement of FASD diagnostic criteria. METHODS: Six databases were searched (inception-February 2023). Case-controls or cohort studies examining associations between participants with/without PAE or a FASD diagnosis and the domains of physical size, dysmorphology, functional neurodevelopment and/or brain structure/neurology were included. Excluded studies were non-empirical, sample size < 10, PAE determined via biological markers only, or no suitable comparison group. Summary data were extracted and associations between outcomes and standardised levels of PAE or FASD diagnosis determined using random-effects meta-analyses. Certainty of the evidence was assessed using GRADE. RESULTS: Of the 306 included studies, 106 reported physical size, 43 dysmorphology, 195 functional neurodevelopment and 110 structural/neurological outcomes, with 292 different outcomes examined. There was a dose-response relationship between PAE and head circumference, as well as measures of physical size, particularly at birth. There was also an association between higher PAE levels and characteristic sentinel facial dysmorphology, as well as many of the current functional neurodevelopmental outcomes considered during diagnosis. However, data were often lacking across the full range of exposures. There was a lack of evidence from studies examining PAE to support inclusion of non-sentinel dysmorphic features, social cognition, speech-sound impairments, neurological conditions, seizures, sensory processing or structural brain abnormalities (via clinical MRI) in diagnostic criteria. GRADE ratings ranged from very low to moderate certainty of evidence. CONCLUSIONS: This comprehensive review provides guidance on which components are most useful to consider in the diagnostic criteria for FASD. It also highlights numerous gaps in the available evidence. Future well-designed pregnancy cohort studies should specifically focus on dose-response relationships between PAE and dysmorphology, neurodevelopment and brain structure/neurological outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021230522.

Toward 3D facial analysis for recognizing Mendelian causes of autism spectrum disorder.

Recognizing Mendelian causes is crucial in molecular diagnostics and counseling for patients with autism spectrum disorder (ASD). We explored facial dysmorphism and facial asymmetry in relation to genetic causes in ASD patients and studied the potential of objective facial phenotyping in discriminating between Mendelian and multifactorial ASD. In a cohort of 152 ASD patients, 3D facial images were used to calculate three metrics: a computational dysmorphism score, a computational asymmetry score, and an expert dysmorphism score. High scores for each of the three metrics were associated with Mendelian causes of ASD. The computational dysmorphism score showed a significant correlation with the average expert dysmorphism score. However, in some patients, different dysmorphism aspects were captured making the metrics potentially complementary. The computational dysmorphism and asymmetry scores both enhanced the individual expert dysmorphism scores in differentiating Mendelian from non-Mendelian cases. Furthermore, the computational asymmetry score enhanced the average expert opinion in predicting a Mendelian cause. By design, our study does not allow to draw conclusions on the actual point-of-care use of 3D facial analysis. Nevertheless, 3D morphometric analysis is promising for developing clinical dysmorphology applications in diagnostics and training.

Re-analysis of whole genome sequencing ends a diagnostic odyssey: Case report of an RNU4-2 related neurodevelopmental disorder.

Despite increasing knowledge of disease-causing genes in human genetics, approximately half of the individuals affected by neurodevelopmental disorders remain genetically undiagnosed. Part of this missing heritability might be caused by genetic variants outside of protein-coding genes, which are not routinely diagnostically investigated. A recent preprint identified de novo variants in the non-coding spliceosomal snRNA gene RNU4-2 as a cause of a frequent novel syndromic neurodevelopmental disorder. Here we mined 164 whole genome sequencing (WGS) trios from individuals with neurodevelopmental or multiple congenital anomaly disorders that received diagnostic genomic investigations at our clinic. We identify a recurrent de novo RNU4-2 variant (NR_003137.2(RNU4-2):n.64_65insT) in a 5-year-old girl with severe global developmental delay, hypotonia, microcephaly, and seizures that likely explains her phenotype, given that extensive previous genetic investigations failed to identify an alternative cause. We present detailed phenotyping of the individual obtained during a 5-year follow-up. This includes photographs showing recognizable facial features for this novel disorder, which might allow prioritizing other currently unexplained affected individuals sharing similar facial features for targeted investigations of RNU4-2. This case illustrates the power of re-analysis to solve previously unexplained cases even when a diagnostic genome remains negative.

Personal journeys to and in human genetics and dysmorphology.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.

Application of the Face2Gene tool in an Italian dysmorphological pediatric clinic: Retrospective validation and future perspectives.

Neurodevelopmental disorders exhibit recurrent facial features that can suggest the genetic diagnosis at a glance, but recognizing subtle dysmorphisms is a specialized skill that requires very long training. Face2Gene (FDNA Inc) is an innovative computer-aided phenotyping tool that analyses patient's portraits and suggests 30 candidate syndromes with similar morphology in a prioritized list. We hypothesized that the software could support even expert physicians in the diagnostic workup of genetic conditions. In this study, we assessed the performance of Face2Gene in an Italian dysmorphological pediatrics clinic. We uploaded two-dimensional face pictures of 145 children affected by genetic conditions with typical phenotypic traits. All diagnoses were previously confirmed by cytogenetic or molecular tests. Overall, the software's differential included the correct syndrome in most cases (98%). We evaluated the efficiency of the algorithm even considering the rareness of the genetic conditions. All "common" diagnoses were correctly identified, most of them with high diagnostic accuracy (93% in top-3 matches). Finally, the performance for the most common pediatric syndromes was calculated. Face2Gene performed well even for ultra-rare genetic conditions (75% within top-3 matches and 83% within top-10 matches). Expert geneticists maybe do not need computer support to recognize common syndromes, but our results prove that the tool can be useful not only for general pediatricians but also in dysmorphological clinics for ultra-rare genetic conditions.

Skeletal Growth Arrest Lines in Fetal Remains: Histopathology and Correlative Placental Pathology.

INTRODUCTION: Skeletal growth arrest lines (GAL) are transverse lines of metaphyseal radiodensity accompanying episodic severe physiological stress. They are poorly described in fetal remains. MATERIALS AND METHODS: We searched our autopsy practice for instances of fetal GAL in post mortem radiology, and correlated them with long bone histology and placental pathology. We describe the appearance, distribution, and pathology of GAL in a cohort of fetal autopsies, and compare the placental pathology accompanying GAL to the placental pathology of asymmetrical growth restriction (AGR) in the same time period. RESULTS: In 2108 consecutive fetal post mortems, we found 20 cases with GAL. About 16 were in singletons with AGR. In these 16, the distribution of placental pathologies was similar to a contemporaneous cohort of 113 cases with AGR. Of the remaining 4, two twins out of 9 sets of monochorionic twins with AGR demonstrated GAL. One case of GAL had symmetrical growth restriction with cytomegalovirus infection, and one case had no AGR and an old, unexplained retroplacental hemorrhage. On histology, GAL are characterized by a region of mineralized chondroid, which is variably incorporated into irregular trabecular bone. DISCUSSION: GALs accompany a variety of placental pathologies and twin-twin transfusion, suggesting episodic disease progression.

CLPB Deficiency Associated Neonatal Cavitating Leukoencephalopathy: A Potential Pathomechanism Underlying Neurologic Disorder.

Caseinolytic peptidase B homolog (CLPB) is a mitochondrial protein which is highly expressed in brain. Its deficiency may be associated with severe neonatal encephalopathy. This report describes a case of fatal neonatal encephalopathy associated with biallelic stop-gain mutation in CLPB (NM_001258392.3:c.1159C>T/p.Arg387*). Neurologic disorder encompasses pre- and post-natal features including polyhydramnios, intrauterine growth restriction, respiratory insufficiency, lethargy, excessive startle reflex, generalized hypertonia, and epileptic seizures. Brain macroscopic examination demonstrates frontal severe periventricular cystic leukoencephalopathy, along with mild ex-vacuo tri-ventricular dilatation. The most striking immunohistopathologic features are striato-thalamic neurodegeneration and deep white matter loss associated with strong reactive astrogliosis. This report supports that CLPB deficiency should be considered among the neurometabolic disorders associated with severe prenatal-onset neurologic impairment that may result from cystic leukoencephalopathy.

What Can Really Be Considered a Syndrome? An Insight Based on 16p11.2 Microduplication.

What is the definition of Syndrome? Since the beginning of studies in genetics, certain terminologies have been created and used to define groups of diseases or alterations. With the advancement of knowledge and the emergence of new technologies, the use of basic concepts is being done in a mistaken or often confusing way. Because of this, revisiting and readjusting the old terms becomes imminent. Here, we explore these concepts and their use, through a literature compilation of an already well-defined genetic alteration (16q11.2 microduplication). We bring comparisons in clinical and molecular scope of the alteration itself and its diagnostic methods, to improve the report of cases, rescuing terminologies and their applicability nowadays.

Human metaphase II oocytes with narrow perivitelline space have poor fertilization, developmental, and pregnancy potentials.

PURPOSE: To analyze the fertilization, developmental, and pregnancy potentials in oocytes with narrow perivitelline space. METHODS: Perivitelline space (PVS) of oocytes was evaluated at the time of ICSI, and those without sufficient PVS were judged as oocytes with narrow PVS (NPVS oocytes), and those with sufficient PVS formation were judged as oocytes with non-narrow PVS (non-NPVS oocytes). The analysis included 634 NPVS oocytes from 278 cycles and 12,121 non-NPVS oocytes from 1698 cycles. The fertilization and developmental potentials of NPVS and non-NPVS oocytes were compared by calculating odds ratios using a mixed-effects logistic regression model. We also compared the embryo transfer outcomes of those used for single vitrified-warmed blastocyst transfer after developing into the blastocyst stage. RESULTS: NPVS oocytes had higher odds ratios for degeneration (adjusted odds ratio [aOR], 1.555; 95% confidence interval [CI], 1.096-2.206; p = 0.0133) and 0PN (aOR, 1.387; 95% CI, 1.083-1.775; p = 0.0095), resulting in a lower 2PN rate (aOR, 0.761; 95% CI, 0.623-0.929; p = 0.0072). Even embryos with confirmed 2PN had lower odds ratios for cleavage (aOR, 0.501; 95% CI, 0.294-0.853; p = 0.0109) and blastocyst development (Gardner criteria; CC-AA) rates (aOR, 0.612; 95% CI, 0.476-0.788; p = 0.0001). Blastocysts developed from NPVS oocytes had significantly lower odds ratios for clinical pregnancy (aOR, 0.435; 95% CI, 0.222-0.854; p = 0.0156) than those developed from non-NPVS oocytes. CONCLUSIONS: Oocytes with NPVS have low fertilization and developmental potential, as well as low likelihood of pregnancy.

Chin Dysmorphology in the Primary Rhinoplasty Population: Prevalence, Objective Analysis, and Implications.

BACKGROUND: Chin flaws are far more common than recognized. Denial of genioplasty by parents or adult patients can present a surgical planning enigma, especially in patients with microgenia and chin deviation. This study aims to investigate the frequency of chin imperfections on patients seeking rhinoplasty, review the conundrum they generate, and offer management suggestions based on over 40 years of the senior author's experience. METHODS: This review included 108 consecutive patients presenting for primary rhinoplasty. Demographics, soft tissue cephalometrics, and surgical details were obtained. Exclusion criteria included prior orthognathic or isolated chin surgery, mandiblular trauma, or congenital craniofacial deformities. RESULTS: Of the 108 patients, 92 (85.2%) were female. Mean age was 30.8 years (SD±13, range 14-72). Ninety-seven (89.8%) patients exhibited some degree of objective chin dysmorphology. Fifteen (13.9%) had Class I deformities (macrogenia), 63 (58.3%) Class II (microgenia), and 14 (12.9%) Class III (combined macro and microgenia in the horizontal or vertical vectors). Forty-one (38%) patients had Class IV deformities (asymmetry). While all patients were offered the opportunity to correct chin flaws, only 11 (10.1%) underwent such procedures. Five (4.6%) patients had simultaneous osseous genioplasty (mean advancement 7.8mm, range 5-9mm); 7 (6.5%) received fat grafting to the chin (mean volume 4.4cc, range 1-9cc). CONCLUSIONS: A considerable proportion of primary rhinoplasty patients possess quantifiable chin dysmorphology on circumspect examination, high-resolution photographs and cephalometric analysis. Only a small number agree to surgical interventions that pursue full facial harmony. Potential reasons for these findings, patient aversion, and mitigation strategies will be discussed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Shared Decision-Making: Process for Design and Implementation of a Decision Aid for Patients With Craniosynostosis.

To describe the process of developing a craniosynostosis decision aid.We conducted a mixed-methods exploratory study between August 2019 and March 2020 to develop a decision aid about surgical treatment for single suture craniosynostosis.A single tertiary care academic children's hospital.The decision aid development team consisted of surgeons, research fellows, a clinical nurse practitioner, clinical researchers with expertise in decision science, and a university-affiliated design school. Qualitative interviews (N = 5) were performed with families, clinicians (N = 2), and a helmeting orthotist to provide feedback on decision aid content, format, and usability.After cycles of revisions and iterations, 3 related decision aids were designed and approved by the marketing arm of our institution. Distinct booklets were created to enable focused discussion of treatment options for the 3 major types of single suture craniosynostosis (sagittal, metopic, unicoronal).Three decision aids representing the 3 most common forms of single suture craniosynostosis were developed. Clinicians found the decision aids could help facilitate discussions about families' treatment preferences, goals, and concerns.We developed a customizable decision aid for single suture craniosynostosis treatment options. This tool lays the foundation for shared decision-making by assessing family preferences and providing clear, concise, and credible information regarding surgical treatment. Future research can evaluate this tool's impact on patient-clinician discussions about families' goals and preferences for treatment.

Midline Cervical Cleft: Case Report and Current Understanding.

Congenital midline cervical cleft (CMCC) is an extraordinarily rare midline lesion that is present at birth. The lesion can cause micrognathia and cervical contracture via underlying traction on the mandible. It is essential to recognize the condition and excise the lesion within 1 year of diagnosis to mitigate long term cosmetic and functional problems. We report a 10-month-old male infant with CMCC diagnosed immediately after birth. Ultrasound with color doppler imaging confirmed the anatomic characteristics of the lesion. The lesion was surgically excised and closed in layers, with no postoperative complications and good functional and cosmetic results. The pathognomonic presentation, etiology, differential diagnosis, and optimal surgical approach are also discussed.

Frem1 activity is regulated by Sonic hedgehog signaling in the cranial neural crest mesenchyme during midfacial morphogenesis.

BACKGROUND: Frem1 has been linked to human face shape variation, dysmorphology, and malformation, but little is known about its regulation and biological role in facial development. RESULTS: During midfacial morphogenesis in mice, we observed Frem1 expression in the embryonic growth centers that form the median upper lip, nose, and palate. Expansive spatial gradients of Frem1 expression in the cranial neural crest cell (cNCC) mesenchyme of these tissues suggested transcriptional regulation by a secreted morphogen. Accordingly, Frem1 expression paralleled that of the conserved Sonic Hedgehog (Shh) target gene Gli1 in the cNCC mesenchyme. Suggesting direct transcriptional regulation by Shh signaling, we found that Frem1 expression is induced by SHH ligand stimulation or downstream pathway activation in cNCCs and observed GLI transcription factor binding at the Frem1 transcriptional start site during midfacial morphogenesis. Finally, we found that FREM1 is sufficient to induce cNCC proliferation in a concentration-dependent manner and that Shh pathway antagonism reduces Frem1 expression during pathogenesis of midfacial hypoplasia. CONCLUSIONS: By demonstrating that the Shh signaling pathway regulates Frem1 expression in cNCCs, these findings provide novel insight into the mechanisms underlying variation in midfacial morphogenesis.

Perspectives on the future of dysmorphology.

The field of clinical genetics and genomics continues to evolve. In the past few decades, milestones like the initial sequencing of the human genome, dramatic changes in sequencing technologies, and the introduction of artificial intelligence, have upended the field and offered fascinating new insights. Though difficult to predict the precise paths the field will follow, rapid change may continue to be inevitable. Within genetics, the practice of dysmorphology, as defined by pioneering geneticist David W. Smith in the 1960s as "the study of, or general subject of abnormal development of tissue form" has also been affected by technological advances as well as more general trends in biomedicine. To address possibilities, potential, and perils regarding the future of dysmorphology, a group of clinical geneticists, representing different career stages, areas of focus, and geographic regions, have contributed to this piece by providing insights about how the practice of dysmorphology will develop over the next several decades.

An automatic facial landmarking for children with rare diseases.

Two to three thousand syndromes modify facial features: their screening requires the eye of an expert in dysmorphology. A widely used tool in shape characterization is geometric morphometrics based on landmarks, which are precise and reproducible anatomical points. Landmark positioning is user dependent and time consuming. Many automatic landmarking tools are currently available but do not work for children, because they have mainly been trained using photographic databases of healthy adults. Here, we developed a method for building an automatic landmarking pipeline for frontal and lateral facial photographs as well as photographs of external ears. We evaluated the algorithm on patients diagnosed with Treacher Collins (TC) syndrome as it is the most frequent mandibulofacial dysostosis in humans and is clinically recognizable although highly variable in severity. We extracted photographs from the photographic database of the maxillofacial surgery and plastic surgery department of Hôpital Necker-Enfants Malades in Paris, France with the diagnosis of TC syndrome. The control group was built from children admitted for craniofacial trauma or skin lesions. After testing two methods of object detection by bounding boxes, a Haar Cascade-based tool and a Faster Region-based Convolutional Neural Network (Faster R-CNN)-based tool, we evaluated three different automatic annotation algorithms: the patch-based active appearance model (AAM), the holistic AAM, and the constrained local model (CLM). The final error corresponding to the distance between the points placed by automatic annotation and those placed by manual annotation was reported. We included, respectively, 1664, 2044, and 1375 manually annotated frontal, profile, and ear photographs. Object recognition was optimized with the Faster R-CNN-based detector. The best annotation model was the patch-based AAM (p < 0.001 for frontal faces, p = 0.082 for profile faces and p < 0.001 for ears). This automatic annotation model resulted in the same classification performance as manually annotated data. Pretraining on public photographs did not improve the performance of the model. We defined a pipeline to create automatic annotation models adapted to faces with congenital anomalies, an essential prerequisite for research in dysmorphology.

Severe Ciliopathy-Like Phenotype in an Infant With a Novel MPDU1 Missense Variant.

Congenital disorders of glycosylation (CDG) are associated with ciliary dysfunction due to altered glycosylation of ciliary glycoproteins. We describe a severe ciliopathy-like phenotype in a female infant associated with a novel homozygous missense variant NM_004870.4(MPDU1):c.503G>A/p.Gly168Glu. Our findings, based on the co-segregation of the variant with the phenotype and in-silico analysis, implicate this MPDU1 missense variant in this disorder. Matched phenotype includes symmetric growth restriction, facial dysmorphism, ichthyosis, hepatomegaly with severe duct plate malformation, renal cortical tubular and glomerular cysts, moderate cerebral tetraventricular dilatation, and severe pontocerebellar hypoplasia. According to this observation, CDG should be included in the workup of infantile ciliopathy-like disorder.

Acquired hump of the corpus callosum: a rare morphologic complication after CSF shunting.

PURPOSE: To present the longitudinal MR imaging of 4 children with an acquired corpus callosum hump, in order to demonstrate graphically that this represents a dysmorphology caused through a constellation of pre-existing pathology, timing, and complications of treatment. MATERIALS AND METHODS: Four cases with a corpus callosum hump were evaluated for common findings in the clinical history and on MRI scans. Those patients with available follow-up imaging were specifically evaluated for the presence of the hump on initial neonatal imaging and for evidence of development and progression of the deformity over time. Corpus callosum length was measured and compared against normal standards. RESULTS AND CONCLUSION: Congenital hydrocephalus, chronic ventricular over-shunting, white matter volume loss, and lateral ventricle communication were common to all cases. Corpus callosum length was above normal values. The corpus callosum hump term was previously described as dysplasia but was not present on initial scans in our cases. We conclude that the corpus callosum hump can be acquired as a complication of over-shunting in children with congenital hydrocephalus. Thus, we present our examples as "acquired hump of the corpus callosum," which differs from the prior example. We postulate that the lengthening of the stretched corpus callosum due to chronic hydrocephalus in the pre-myelinated state renders it unable to return to its normal shape when the ventricles are drained. Over-shunting of both lateral ventricles simultaneously in the absence of a septum pellucidum results in collapse and folding in of the corpus callosum on itself, resulting in the hump.

Prevalence of neural tube defects among pregnant women in Addis Ababa: a community-based study using prenatal ultrasound examination.

PURPOSE: The primary aim of this study was to estimate the prevalence of NTDs at ultrasound examination in communities of Addis Ababa and secondarily to provide a description of the dysmorphology of the NTD cases. METHODS: We enrolled 958 pregnant women from 20 randomly selected health centers in Addis Ababa during the period from October 1, 2018, to April 30, 2019. Of these 958 women, 891 had an ultrasound examination after enrollment, with a special focus on NTDs. We estimated the prevalence of NTDs and compared it with previously reported hospital-based birth prevalence estimates from Addis Ababa. RESULTS: Among 891 women, 13 had twin pregnancies. We identified 15 NTD cases among 904 fetuses, corresponding to an ultrasound-based prevalence of 166 per 10,000 (95% CI: 100-274). There were no NTD cases among the 26 twins. Eleven had spina bifida (122 per 10,000, 95% CI: 67-219). Among the 11 fetuses with spina bifida, three had a cervical and one had a thoracolumbar defect while the anatomical site for 7 was not registered. Seven of the 11 spina bifida defects had skin covering, while two of the cervical lesions were uncovered. CONCLUSION: We report a high prevalence of NTDs among pregnancies in communities of Addis Ababa based on screening by ultrasound. The prevalence was higher than in previous hospital-based studies in Addis, and the prevalence of spina bifida was particularly high.

3D Photography to Quantify the Severity of Metopic Craniosynostosis.

This study aims to determine the utility of 3D photography for evaluating the severity of metopic craniosynostosis (MCS) using a validated, supervised machine learning (ML) algorithm.This single-center retrospective cohort study included patients who were evaluated at our tertiary care center for MCS from 2016 to 2020 and underwent both head CT and 3D photography within a 2-month period.The analysis method builds on our previously established ML algorithm for evaluating MCS severity using skull shape from CT scans. In this study, we regress the model to analyze 3D photographs and correlate the severity scores from both imaging modalities.14 patients met inclusion criteria, 64.3% male (n = 9). The mean age in years at 3D photography and CT imaging was 0.97 and 0.94, respectively. Ten patient images were obtained preoperatively, and 4 patients did not require surgery. The severity prediction of the ML algorithm correlates closely when comparing the 3D photographs to CT bone data (Spearman correlation coefficient [SCC] r = 0.75; Pearson correlation coefficient [PCC] r = 0.82).The results of this study show that 3D photography is a valid alternative to CT for evaluation of head shape in MCS. Its use will provide an objective, quantifiable means of assessing outcomes in a rigorous manner while decreasing radiation exposure in this patient population.

Mandibular Radiomorphometric Characteristics of Individuals with Bilateral or Unilateral Cleft Lip and Palate.

OBJECTIVE: This study aimed to investigate and compare the mandibular radiomorphometric characteristics of patients with unilateral or bilateral cleft lip and palate (CLP) with those of individuals without CLP and to determine whether there was a difference. DESIGN: Retrospective cohort study. SETTING: Orthodontic Department in Faculty of Dentistry. PATIENTS AND INTERVENTIONS: Mandibular cortical bone thickness was measured on high-quality panoramic radiographs taken from 46 patients with unilateral or bilateral CLP aged 13-15 years and 21 control patients. MAIN OUTCOME MEASURES: Three radiomorphometric indices [antegonial index (AI), mental index (MI), and panoramic mandibular index (PMI)] were measured bilaterally. AutoCAD software was used for MI, PMI, and AI measurements. RESULTS: Left MI values were significantly lower in individuals with unilateral cleft lip and palate (UCLP; 0.029 ± 0.04) than in individuals with bilateral cleft lip and palate (BCLP; 0.033 ± 0.07). In addition, right MI values of individuals with right UCLP (0.26 ± 0.06) were significantly lower than those of individuals with left UCLP (0.34 ± 0.06) or BCLP (0.32 ± 0.08). No difference was observed between individuals with BCLP and left UCLP. These values did not differ between groups. CONCLUSIONS: Antegonial index and PMI values did not differ between individuals with different types of CLP or when compared with control patients. In patients with UCLP, cortical bone thickness was found to be reduced on the cleft side compared to the intact side. Patients with UCLP with a right-sided cleft had a more substantial decrease in cortical bone thickness.