Search

Background: Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD). Objectives: To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels. Methods: 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC. Results: Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001). Conclusions: We replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way. [ABSTRACT FROM AUTHOR]

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants. [Display omitted] Boonsawat et al. establish germline missense variants in the tumor suppressor gene ZNRF3 as a cause of neurodevelopmental disorders (NDDs) with microcephaly or macrocephaly, depending on the functional/domain-specific effects of the variants on Wnt/β-catenin signaling. This study finds that ZNRF3 haploinsufficiency does not cause NDDs but rather other phenotypes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Identifying novel variants in very rare disease genes can be challenging when patients exhibit a complex phenotype that expands the one described, and we provide such an example here. A few terminal truncating variants in KIDINS220 cause spastic paraplegia (SP), intellectual disability (ID), nystagmus, and obesity (SINO, MIM #617296). Prompted by the result of next-generation sequencing on a patient referred for SP associated with complex brain dysmorphisms, we reviewed the phenotype of SINO patients focusing on their brain malformations, mainly described in prenatal age and first years of life, and tried to understand if the predicted effect of the mutant kidins220 may have caused them. Methods: We performed whole exome sequencing (WES) and a literature and mutation databases review. Results: We report a young adult with SP, severe ID, strabismus, and macrocephaly exhibiting brain malformations at follow-up, partially overlapping with those described in TUBB3 tubulinopathy. WES analysis of the proband and parents identified the heterozygous de novo variant (NM_020738.4: c. 4144G > T) p. Glu 1382* in KIDINS220 that was predicted to be causative of SINO. Conclusions: The progression of myelination and the development of brain structures turned out to be crucial for identifying, at follow-up, the whole KIDINS220-related brain malformations. The truncated proteins associated with SINO lack a portion fundamental for the interaction of kidins220 with tubulins and microtubule-associated proteins. The complexity of the brain malformations displayed by our patient, and possibly by other reported SINO patients, could result from an impaired dynamic modulation of the microtubule cytoskeleton during embryogenesis. Brain malformations must be considered as part of the SINO spectrum phenotype. [ABSTRACT FROM AUTHOR]

The etiology of neurodevelopmental disorders and epilepsy is very heterogeneous and partly still unknown, and the research of causative genes related to these diseases is still in progress. In 2020, pathogenic variants of the TET3 gene were associated with Beck–Fahrner syndrome, which is characterized by neurodevelopmental delay, intellectual and learning disabilities of variable degree, growth abnormalities, hypotonia and seizures. Variants of TET3 have been described having both an autosomal dominant with a milder phenotype and an autosomal recessive pattern. To date, in the literature, only 28 patients are reported with pathogenic variants of the TET3 gene, and only 9 of them have epilepsy. We describe a 31-year-old woman with macrocephaly, mild neurodevelopmental delay and a long history of epilepsy. Trio-based exome sequencing identified a de novo heterozygous TET3 variant, c.2867G>A p.(Arg956Gln), never described before, absent in the general population and predicted to be potentially pathogenetic by bioinformatics tools. This report aims to describe the clinical history of our patient, the pharmacological treatment and clinical response, as well as the biological characteristics of this new variant. [ABSTRACT FROM AUTHOR]

Imagawa-Matsumoto syndrome (IMMAS; MIM #618786) is an autosomal dominant syndrome characterized by overgrowth, dysmorphic features, musculoskeletal abnormalities, developmental delay, and intellectual disability. The first case was reported in 2017 and has subsequently been diagnosed in only another 12 patients. We also present the first IMMAS patient from Turkey. A 19-year-old female was admitted to the neurology outpatient clinic due to a behavioral disorder and intellectual disability. Her physical examination revealed macrocephaly and dysmorphic features like a round face, broad forehead, hypertelorism, and variable skeletal anomalies such as flat feet, clinodactyly, and macrocephaly. Cranial magnetic resonance imaging (MRI) showed agenesis of the corpus callosum and polymicrogyria. Chromosomal analysis results were consistent with a normal constitutional female karyotype and microarray analysis showed a de novo 1.5-MB size deletion on the long arm of chromosome 17; band q11.2 encompassing the Polycomb Repressive Complex 2 Subunit (SUZ12 gene, MIM *606245). This report will contribute to the limited information in the literature. [ABSTRACT FROM AUTHOR]

Abstract Background Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD). Objectives To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels. Methods 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC. Results Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p

Fetal intracranial teratoma presents a rare and devastating diagnosis. Typically, this condition is first detected during routine prenatal ultrasounds, appearing as an irregular heterogeneous lesion. Further insights are gained through fetal magnetic resonance imaging (MRI), better characterizing the anomaly. The combination of these modalities provides detail-oriented high resolution MRI images, while follow-up ultrasounds capture dynamic growth changes, serving as a cost-effective and easily accessible adjunct. This fast-growing tumor leads to macrocephaly and ventriculomegaly, causing severe distortion of the brain parenchyma. Early detection is crucial for effective fetal management and preventing maternal complications. Unfortunately, treatment options are limited due to the tumor's aggressive nature, typically resulting in fetal demise shortly after birth. Here, we present the sonographic and MRI findings of a congenital intracranial teratoma, reaching massive proportions and replacing the entire cerebral hemisphere.

Protein phosphatase 2 regulatory subunit B56δ related neurodevelopmental disorder (PPP2R5D‐related NDD) is largely caused by de novo heterozygous missense PPP2R5D variants. We report medical characteristics, longitudinal adaptive functioning, and in‐person neurological, motor, cognitive, and electroencephalogram (EEG) activity for PPP2R5D‐related NDD. Forty‐two individuals (median age 6 years, range = 0.8–25.3) with pathogenic/likely pathogenic PPP2R5D variants were assessed, and almost all variants were missense (97.6%) and de novo (85.7%). Common clinical symptoms were developmental delay, hypotonia, macrocephaly, seizures, autism, behavioral challenges, and sleep problems. The mean Gross motor functional measure‐66 was 60.2 ± 17.3% and the mean Revised upper limb module score was 25.9 ± 8.8. The Vineland‐3 adaptive behavior composite score (VABS‐3 ABC) at baseline was low (M = 61.7 ± 16.8). VABS‐3 growth scale value scores increased from baseline in all subdomains (range = 0.6–5.9) after a mean follow‐up of 1.3 ± 0.3 years. EEG beta and gamma power were negatively correlated with VABS‐3 score; p < 0.05. Individuals had a mean Quality‐of‐life inventory‐disability score of 74.7 ± 11.4. Twenty caregivers (80%) had a risk of burnout based on the Caregiver burden inventory. Overall, the most common clinical manifestations of PPP2R5D‐related NDD were impaired cognitive, adaptive function, and motor skills; and EEG activity was associated with adaptive functioning. This clinical characterization describes the natural history in preparation for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Macrocephaly is described in almost 15% of children with Autism Spectrum Disorder (ASD). Relationships between head growth trajectories and clinical findings in ASD children show a high degree of variability, highlighting the complex heterogeneity of the disorder. Objectives: The aim of this study was to measure differences of the early growth trajectory of head circumference (HC) in children with ASD and macrocephaly compared to ASD normocephalic children, examining clinical correlates in the two groups of patients. Methods: HC data were collected from birth to 5 years of age in a sample of children with a confirmed diagnosis of ASD. Participants were classified into two groups: ASD macrocephaly (ASD-M, Z-scores =1.88 in at least two consecutive HC measurements), and ASD non-macrocephaly (ASD-N). Based on the distribution of HC measurements (Z-scores), five age groups were identified for the longitudinal study. Developmental and behavioral characteristics of the ASD-M children compared to the ASD-N group were compared by using standardized scores. Results: 20,8% of the children sample met criteria for macrocephaly. HC values became indicative of macrocephaly in the ASD-M group at the age range from 1 to 6 months, and persisted thereafter throughout the first five years of age. ASDM children showed significantly higher developmental quotients of Griffiths III B and D subscales compared to ASD-N group. No significant differences in the severity of ASD symptoms assessed by ADOS-2 were observed between ASD-M and ASD-N groups. Conclusion: In this study HC size from birth to 5 years links to accelerated HC growth rate as early as the first 6 months of age in children with ASD and macrocephaly, preceding the onset and diagnosis of ASD. We found that in early childhood, children with ASD-M may exhibit some advantages in language and social communication and emotional skills without differences in autism severity, when compared with age-matched normocephalic ASD children. Longitudinal analyses are required to catch-up prospectively possible relationships between head size as proxy measure of brain development and neuro-developmental and behavioral features in children with ASD. [ABSTRACT FROM AUTHOR]

Tubulinopathies are associated with malformations of cortical development but not Walker–Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker–Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker–Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker–Warburg-associated genes confirm this as not a new presentation of Walker–Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of. [ABSTRACT FROM AUTHOR]

Objective: To measure the size of jugular foramina in infants affected by external hydrocephalus (EH) and in a control group, to support the hypothesis that a jugular foramen (JF) stenosis may determine dural venous sinus alterations and increased venous outflow resistance as main pathophysiological factor. Methods: Minimum, maximum, and mean values of JF areas were measured in a series of phase-contrast magnetic resonance venous angiography (angio MRV PCA3D) performed on 81 infants affected by EH. Results were compared with a group of 54 controls. Results: Smaller JF area was significantly smaller in patients versus controls (43.1 ± 14.6 vs. 52.7 ± 17.8; p < 0.001) resulting in a significantly smaller mean JF areas in patients vs. controls (51.6 ± 15.8 vs. 57.0 ± 18.3; p = 0.043). In patients, smaller JF areas were significantly associated with higher venous obstruction grading score (VOGS) both on the right (p = 0.018) and on the left side (p = 0.005). Positional plagiocephaly (cranial vault asymmetry index > 3.5%) was more frequent among EH patients than controls (38/17) but the difference was not significant (p = 0.07). In the 38 plagiocephalic patients, JF area was smaller on the flattened side than the contralateral in a significant number of cases both in right (21/7) and left (9/1) plagiocephaly (p < 0.0005) as well as the mean area (48.2 + 16.4 mm2 vs. 57.5 + 20.7 mm2, p = 0.002) and VOGS was significantly higher on the plagiocephalic side than on the contralateral side (1.6 ± 1.1 vs. 1.1 ± 0.9, p = 0.019). Conclusion: In this series of infants affected by EH, the mean size of the ostium of both JF resulted significantly smaller than controls. JF stenosis was significantly associated with higher degrees of venous obstruction on both sides, suggesting a direct extrinsic effect of JF size on dural sinus lumen and possible consequent effect on venous outflow resistance. Positional plagiocephaly, when present, was associated with a decreased JF area and increased VOGS on the flattened side. [ABSTRACT FROM AUTHOR]

Tatton–Brown–Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the DNMT3A gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton–Brown–Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the DNMT3A, leading to the formation of a premature stop codon—NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton–Brown–Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the DNMT3A gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the DNMT3A gene significantly increases the risk of developing acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to provide a full characterization of a cohort of 11 pediatric patients diagnosed with PTEN hamartoma tumor syndrome (PHTS). Patients and methods: Eleven patients with genetic diagnostic of PHTS were recruited between February 2019 and April 2023. Clinical, imaging, demographic, and genetic data were retrospectively collected from their hospital medical history. Results: Regarding clinical manifestations, macrocephaly was the leading sign, present in all patients. Frontal bossing was the most frequent dysmorphism. Neurological issues were present in most patients. Dental malformations were described for the first time, being present in 27% of the patients. Brain MRI showed anomalies in 57% of the patients. No tumoral lesions were present at the time of the study. Regarding genetics, 72% of the alterations were in the tensin-type C2 domain of PTEN protein. We identified four PTEN genetic alterations for the first time. Conclusions: PTEN mutations appear with a wide variety of clinical signs and symptoms, sometimes associated with phenotypes which do not fit classical clinical diagnostic criteria for PHTS. We recommend carrying out a genetic study to establish an early diagnosis in children with significant macrocephaly. This facilitates personalized monitoring and enables anticipation of potential PHTS-related complications. [ABSTRACT FROM AUTHOR]

Thanatophoric dysplasia is a lethal form of skeletal dysplasia seen in neonates. The word ‘thanatophoric’ is derived from the Greek word thanatophorus meaning death bringing. Thanatophoric dysplasia results from mutations within the Fibroblast Growth Factor Receptor 3 (FGFR3) gene which is located on chromosome 4p16.3. A female neonate with dysmorphic features such as macrocephaly, frontal bossing, periorbital swelling and depressed nasal bridge was delivered to a 35year old woman. The upper and lower limbs were short with excessive skin folds. A case of female neonate with thanatophoric dysplasia is hereby reported to raise awareness of this condition and to describe the features of thanatophoric dysplasia seen in this patient .

Tatton–Brown–Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the DNMT3A gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton–Brown–Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the DNMT3A, leading to the formation of a premature stop codon—NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton–Brown–Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the DNMT3A gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the DNMT3A gene significantly increases the risk of developing acute myeloid leukemia.

We present a case of Bannayan-Riley-Ruvalcaba syndrome (BRRS) diagnosed during the treatment of recurrent iron deficiency anemia (IDA). IDA is the most common hematological disorder in children and is often caused by dietary problem or obesity. However, in relatively rare cases, it is caused by gastrointestinal (GI) disease. BRRS is a rare genetic disorder characterized by macrocephaly, multiple noncancerous tumors, intestinal hamartomatous polyps, and penile freckling due to a defect in the PTEN gene. GI polyps can cause chronic GI bleeding, leading to IDA development. We recommend active GI evaluation, including esophagogastroduodenoscopy, for children with recurrent IDA.

Abstract Background Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians’ understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference. Methods Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed. Results In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2. Limitations The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians. Conclusion Some ADOS items may better capture the signs that are most associated with clinicians’ implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments.

Abstract Background Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility. Case presentation We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia. Conclusions To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1-related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects.

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals. [ABSTRACT FROM AUTHOR]

Abusive head trauma (AHT) is a significant cause of morbidity and mortality for infants. Determining when to pursue a complete physical abuse evaluation can be difficult, especially for nonspecific findings or when a child appears clinically well. This retrospective study of 7 cases sought to describe the presentation, evaluation, and diagnoses for infants with abnormal subdural collections identified on cranial ultrasound for macrocephaly, and to determine how frequently AHT is diagnosed. The results of this study showed that while each patient presented due to asymptomatic macrocephaly, the extent of the workup varied greatly. In addition, no infants had suspicious injuries for abuse during the initial evaluation or the year following. In summary, among the 7 patients seen for asymptomatic macrocephaly with possible subdural hemorrhage, there were very inconsistent child abuse workups. There needs to be a standardized clinical guideline for this specific patient population involving a child abuse pediatric evaluation. [ABSTRACT FROM AUTHOR]

Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8 haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact of Chd8 haploinsufficiency on maternal‐offspring interactions. While differences in maternal care as a function of Chd8 genotype have not been studied directly, a previous study showed that pup survival was reduced when reared by Chd8 heterozygous dams compared with wild‐type (WT) dams, suggesting altered maternal care as a function of Chd8 genotype. Through systematic observation of the C57BL/6 strain, we first determined the impact of Chd8 haploinsufficiency in the offspring on WT maternal care frequencies across preweaning development. We next determined the impact of maternal Chd8 haploinsufficiency on pup care. Compared with litters with all WT offspring, WT dams exhibited less frequent maternal behaviors toward litters consisting of offspring with mixed Chd8 genotypes, particularly during postnatal week 1. Dam Chd8 haploinsufficiency decreased litter survival and increased active maternal care also during postnatal week 1. Determining the impact of Chd8 haploinsufficiency on early life experiences provides an important foundation for interpreting offspring outcomes and determining mechanisms that underlie heterogeneous phenotypes. [ABSTRACT FROM AUTHOR]

Background: Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility. Case presentation: We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia. Conclusions: To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1-related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects. [ABSTRACT FROM AUTHOR]

Thauvin‐Robinet‐Faivre syndrome (#617107) is a rare autosomal recessive overgrowth syndrome characterized by intellectual disability, facial dysmorphism, macrocephaly, and variable congenital malformations. It is caused by homozygous or compound heterozygous FIBP gene mutations. The FIBP gene is located on the 11q13.1 region and codes the acidic fibroblast growth factor intracellular binding protein, which is involved in the fibroblast growth factor (FGF) signaling pathway. FGF signaling is required for neurogenesis and neuronal precursor proliferation. The FGF controls cell proliferation, differentiation, and migration in embryonic development and in adult life. Overgrowth syndromes consist of a wide spectrum disorders characterized by prenatal and postnatal excess growth in weight and length, often associated malformations, intellectual disability, and neoplastic predisposition. Embryonic tumors are especially common in these syndromes. Thauvin‐Robinet‐Faivre syndrome is a recently described overgrowth syndrome with typical facial dysmorphic and clinical features. To date, only four patients have been reported with this disorder. Herein, two new cases of Thauvin‐Robinet‐Faivre syndrome are reported with overgrowth, intellectual disability, typical dysmorphic signs in one dysplastic kidney, and a novel homozygous FIBP gene variant. Exome sequencing analysis showed that both affected siblings share the same homozygous c. 412‐3_415dupCAGTTTG FIBP gene variant. Reporting two new cases with this rare autosomal recessive overgrowth syndrome with a novel FIBP gene variant will support and expand the clinical spectrum of Thauvin‐Robinet‐Faivre syndrome. Also discussed will be the function of FIBP in tumorigenesis and the possible renal tumor susceptibility in heterozygous carriers will be emphasized. [ABSTRACT FROM AUTHOR]

BackgroundMacrocephaly is described in almost 15% of children with Autism Spectrum Disorder (ASD). Relationships between head growth trajectories and clinical findings in ASD children show a high degree of variability, highlighting the complex heterogeneity of the disorder.ObjectivesThe aim of this study was to measure differences of the early growth trajectory of head circumference (HC) in children with ASD and macrocephaly compared to ASD normocephalic children, examining clinical correlates in the two groups of patients.MethodsHC data were collected from birth to 5 years of age in a sample of children with a confirmed diagnosis of ASD. Participants were classified into two groups: ASD macrocephaly (ASD-M, Z-scores ≥1.88 in at least two consecutive HC measurements), and ASD non-macrocephaly (ASD-N). Based on the distribution of HC measurements (Z-scores), five age groups were identified for the longitudinal study. Developmental and behavioral characteristics of the ASD-M children compared to the ASD-N group were compared by using standardized scores.Results20,8% of the children sample met criteria for macrocephaly. HC values became indicative of macrocephaly in the ASD-M group at the age range from 1 to 6 months, and persisted thereafter throughout the first five years of age. ASD-M children showed significantly higher developmental quotients of Griffiths III B and D subscales compared to ASD-N group. No significant differences in the severity of ASD symptoms assessed by ADOS-2 were observed between ASD-M and ASD-N groups.ConclusionIn this study HC size from birth to 5 years links to accelerated HC growth rate as early as the first 6 months of age in children with ASD and macrocephaly, preceding the onset and diagnosis of ASD. We found that in early childhood, children with ASD-M may exhibit some advantages in language and social communication and emotional skills without differences in autism severity, when compared with age-matched normocephalic ASD children. Longitudinal analyses are required to catch-up prospectively possible relationships between head size as proxy measure of brain development and neuro-developmental and behavioral features in children with ASD.

The etiology of neurodevelopmental disorders and epilepsy is very heterogeneous and partly still unknown, and the research of causative genes related to these diseases is still in progress. In 2020, pathogenic variants of the TET3 gene were associated with Beck–Fahrner syndrome, which is characterized by neurodevelopmental delay, intellectual and learning disabilities of variable degree, growth abnormalities, hypotonia and seizures. Variants of TET3 have been described having both an autosomal dominant with a milder phenotype and an autosomal recessive pattern. To date, in the literature, only 28 patients are reported with pathogenic variants of the TET3 gene, and only 9 of them have epilepsy. We describe a 31-year-old woman with macrocephaly, mild neurodevelopmental delay and a long history of epilepsy. Trio-based exome sequencing identified a de novo heterozygous TET3 variant, c.2867G>A p.(Arg956Gln), never described before, absent in the general population and predicted to be potentially pathogenetic by bioinformatics tools. This report aims to describe the clinical history of our patient, the pharmacological treatment and clinical response, as well as the biological characteristics of this new variant.

Background: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset macrocephaly. MLC1 has been identified as a main pathogenic gene. Methods: Clinical data such as magnetic resonance imaging (MRI), routine blood tests, and physical examinations were collected from proband. Trio whole‐exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (<0.01) in the exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate variants were validated using Sanger sequencing. Results: Here, we report a new homozygous variant identified in two children from the same family in the MLC1 gene [NM_015166.4: c.838_843delinsATTTTA, (p.Ser280_Phe281delinsIleLeu)]. This variant is classified as variant of uncertain significance (VUS) according to the ACMG guidelines. Further experiments demonstrate that the newly identified variant causes a decrease of MLC1 protein levels when expressed in a heterologous expression system. Conclusion: Our case expands on this genetic variation and provides new evidence for the clinical diagnosis of MLC1‐related MLC. [ABSTRACT FROM AUTHOR]

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity. Harris et al. describe three individuals with overlapping macrocephaly-associated phenotypes carrying a recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). MAXArg60Gln binds its target E-box sequence with a lower affinity, meaning more efficient heterodimerization with c-Myc and dysregulated transcriptional activity. c-Myc inhibitors provide a possible therapeutic option for individuals carrying this variant. [ABSTRACT FROM AUTHOR]

The syndrome of megalencephaly, mega corpus callosum (MEG-MegaCC) accompanied by complete lack of motor development is a rare condition with only few sporadic cases having been reported in the literature. In this paper, we describe a child from non-consanguineous parents presenting with MegaCC, psychomotor retardation, and language impairment linked to MEG-MegaCC syndrome. Genetic analysis, radiological findings, and detailed neurological phenotype of MEG-MegaCC syndrome with its overlapping syndromes would allow for a better classification of the disease spectrum. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We report the first multigenerational family with NFIA‐related disorder from a missense variant. This case highlights the condition's phenotypic variability and the need for genetic testing when an initial diagnosis fails to explain all symptoms. [ABSTRACT FROM AUTHOR]

Abstract Background Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset macrocephaly. MLC1 has been identified as a main pathogenic gene. Methods Clinical data such as magnetic resonance imaging (MRI), routine blood tests, and physical examinations were collected from proband. Trio whole‐exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (

Key Clinical Message We report the first multigenerational family with NFIA‐related disorder from a missense variant. This case highlights the condition's phenotypic variability and the need for genetic testing when an initial diagnosis fails to explain all symptoms.

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

Background: Plagiocephaly is defined as an asymmetrical distortion of the skull, resulting in an oblique trapezoid or parallelogram head shape. Deformational plagiocephaly (DP) is caused by forces acting on one side of the back of the head, distorting normal skull symmetry., Objective: The aims of this systematic review and meta-analysis were to critically assess the evidence for nonobstetric risk factors for DP and to make evidence-based recommendations for reducing the prevalence of DP., Methods: The selection criterion was studies reporting risk factors for DP. Case reviews, case series, expert opinions, and systematic reviews were excluded. PubMed and Web of Science were searched from August 21, 2010, to August 21, 2022. Publication bias was assessed using funnel plots. Meta-analyses were presented using forest plots., Results: A total of 19 studies (cohort studies: n=13, 68%; case-control studies: n=5, 26%; and cross-sectional studies: n=1, 5%) with a total of 14,808 participants were included. Of the 43 investigated potential nonobstetric factors, 16 (37%) were associated with DP. Of these 16 factors, 12 (75%) had odds ratios (ORs) with 95% CIs not crossing 1: insufficient vitamin D intake (OR 7.15, 95% CI 3.77-13.54), head position preference (OR 4.75, 95% CI 3.36-6.73), bottle-only feeding (OR 4.65, 95% CI 2.70-8.00), reduced tummy time (OR 3.51, 95% CI 1.71-7.21), sleeping position (OR 3.12, 95% CI 2.21-4.39), fewer motor milestones reached by the age of 6 months (OR 2.56, 95% CI 1.66-3.96), obesity (OR 2.45, 95% CI 1.02-5.90), maternal education level (OR 1.66, 95% CI 1.17-2.37), male sex (OR 1.51, 95% CI 1.07-2.12), formula feeding (OR 1.51, 95% CI 1.00-2.27), head circumference (OR 1.22, 95% CI 1.06-1.40), and mechanical ventilation (OR 1.10, 95% CI 1.00-1.14). No evidence of publication bias was detected., Conclusions: This study provides a comprehensive assessment of the nonobstetric factors associated with DP and presents 11 evidence-based recommendations for reducing its prevalence. The primary limitation is that only publication bias was assessed., Trial Registration: PROSPERO CRD42020204979; https://www.crd.york.ac.uk/prospero/display&#95;record.php? ID=CRD42020204979., (©Christopher Robert Timothy Hillyar, Natalie Bishop, Anjan Nibber, Frances Jean Bell-Davies, Juling Ong. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 18.09.2024.)

Reduction cranioplasty may be indicated to address functional or cosmetic sequelae of hydrocephalic macrocephaly. With the advent of CAD/CAM digital workflow, surgeons can design and fabricate craniotomy guides, templates, and models that allow for precise cranial reconstruction. Although there are several advantages of virtual planning, pre-determined surgical plans may limit intraoperative flexibility, requiring surgeons to troubleshoot errors in pre-operative planning or model design. The purpose of this report is to present a series of cases demonstrating our institution's technique for single-stage reduction cranioplasty using a CAD/CAM workflow. This report will highlight the benefits and challenges associated with a contemporary digital workflow for reduction cranioplasty., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings., Methods: We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort., Results: These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation., Conclusion: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with rising prevalence, necessitating early diagnosis and intervention. This case report examines the clinical diagnosis approach of ASD in children under two years, emphasizing motor developmental delay, chromosome 19 mutations, prematurity, macrocephaly, and false-negative Modified Checklist for Autism in Toddlers (MCHAT) results. This study identifies gross motor delays as a potential key indicator in the diagnosis of ASD, as all five cases (Patients A, B, C, D, and E) were observed to have such deficits. Two cases (Patients A and B) initially had negative MCHAT results but were later diagnosed with ASD. Patients C and E both had a chromosome 19 abnormality. Patient E had macrocephaly and an amino acid metabolism disorder. ASD atypical behaviors like hand flapping, wringing, and twirling were also noted. Our systematic review validated the key findings presented in this study, unveiling a consistent pattern throughout the existing literature about ASD diagnoses and the associated misconceptions. These cases highlight the significance of early motor delay, genetic factors, and the limitations of MCHAT in early ASD diagnosis. This case report underscores the need for improved screening tools, genetic investigations, and comprehensive assessments to enhance early detection and intervention for ASD. Early identification and personalized interventions hold a promise to improve the outcomes and quality of life for children with autism., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fernandez et al.)

Introduction: Inherited 5-oxoprolinase (OPLAH) deficiency is a rare inborn condition characterized by 5-oxoprolinuria. The inherited condition of 5-oxoprolinuria, or pyroglutamic aciduria, is primarily caused by mutations in the genes that encode glutathione synthetase (GSS) and 5-oxoprolinase (OPLAH), which are enzymes involved in the gamma-glutamyl cycle in glutathione metabolism. We report a 3-year-old male patient with epilepsy and speech difficulty diagnosed as primary 5-oxoprolinuria due to a novel OPLAH gene mutation., Case Presentation: A 3-year-old boy who was delivered at full term in an uncomplicated birth to consanguineous parents presented with epilepsy at the age of 2 years. He did not speak fluently. He was using 5-10 words with decreased language fluency. His past medical history revealed postnatal macrocephaly, hydrocephalus, and well-controlled epilepsy with levetiracetam. Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia were striking features in brain MRI. A urine sample was sent for organic acid analysis by gas chromatography-mass spectrometry (GC-MS); quantitation of 5-oxoproline by stable isotope dilution gave a value of 177.9 mmol/mol creatinine (reference values 25.8-92.2). Molecular genetic analysis of the OPLAH gene revealed a novel homozygous variant ( OPLAH (NM&#95;017570.5): c.1909C>T p.Arg637Trp)., Conclusion: We conclude that inherited 5-oxoprolinase deficiency is not a benign biochemical condition, and patients with 5-oxoprolinuria should be screened for it. The nature of this inherited metabolic disorder must be determined through long-term observation. We wish to emphasize the significance of molecular genetic analysis in symptomatic patients with persistently elevated levels of 5-oxoproline in the urine, as measured by organic acid analysis., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 S. Karger AG, Basel.)

Introduction: Primrose syndrome (PS; MIM #259050) is a rare autosomal dominant genetic condition characterized by macrocephaly with or without tall stature, hypotonia, moderate to severe intellectual disability (ID) with delay in expressive speech development, behavioral abnormalities, and a recognizable facial phenotype including deep set eyes, ptosis, narrow and frequently downslanting palpebral fissures, and depressed nasal bridge. PS is caused by a heterozygous pathogenic variant in ZBTB20 (MIM #606025) on chromosome 3q13. Among other characteristic findings are ocular abnormalities, hearing loss, calcification of the external ear cartilage, nonspecific brain magnetic resonance imaging findings, and cryptorchidism. Adults may exhibit joint contractures, distal muscle wasting, sparse body hair, cataract, and disturbed glucose metabolism as well. The majority of affected individuals have typically been adults until recently since the phenotype becomes more recognizable in time., Case Presentation: In this study, we report on a 14-month-old girl who presented with neurodevelopmental findings, facial features, and hearing loss. The glucose metabolism was normal, and muscle atrophy, joint contractures, and external ear cartilage calcification were yet hitherto not evident. A novel de novo missense variant in ZBTB20 was identified with the aid of exome sequencing., Conclusion: PS is a rare clinical entity with various recognizable features, yet the phenotype may be indistinguishable from other neurodevelopmental disorders. Exome sequencing is a useful diagnostic tool especially in patients with no specific diagnosis despite detailed examinations and imaging studies., Competing Interests: The authors declare that they have no conflict of interests., (© 2024 S. Karger AG, Basel.)

Fetal intracranial teratoma presents a rare and devastating diagnosis. Typically, this condition is first detected during routine prenatal ultrasounds, appearing as an irregular heterogeneous lesion. Further insights are gained through fetal magnetic resonance imaging (MRI), better characterizing the anomaly. The combination of these modalities provides detail-oriented high resolution MRI images, while follow-up ultrasounds capture dynamic growth changes, serving as a cost-effective and easily accessible adjunct. This fast-growing tumor leads to macrocephaly and ventriculomegaly, causing severe distortion of the brain parenchyma. Early detection is crucial for effective fetal management and preventing maternal complications. Unfortunately, treatment options are limited due to the tumor's aggressive nature, typically resulting in fetal demise shortly after birth. Here, we present the sonographic and MRI findings of a congenital intracranial teratoma, reaching massive proportions and replacing the entire cerebral hemisphere., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Cowden syndrome (CS) is a rare autosomal dominant genodermatosis disorder. This disease is characterized by the development of several hamartomata lesions in a variety of tissues from all three embryonic layers. The most well-known hamartomata are those of the gastrointestinal system, which represent one of the major criteria for the diagnosis of CS. Yet, the most frequent initial presenting symptom of the disease is thought to be mucocutaneous symptoms such as trichilemmomas, acral keratosis, and oral papilloma. Early diagnosis and management are essential to improving the quality of life for patients with CS as this disorder predisposes them to cancers such as thyroid, breast, gastrointestinal, and endometrial cancers. This report presents a rare case of CS in a Bahraini child who presented with macrocephaly and had numerous intestinal polyposis. Genetic testing using whole exome sequencing confirmed the diagnosis, identifying a pathogenic de novo phosphatase and tensin homolog gene ( PTEN ) variant (Chr10 NM&#95;000314.8: c.17&#95;18del p.(Lys6Argfs*4)) in a heterozygous state. This variant has been confirmed by Sanger sequencing., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Research and Research Ethics Committee, Goverment Hospitals, Manama, Bahrain issued approval 66-050624. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Isa et al.)

Atrichia with papular lesions (APL) is a hair abnormality characterized by loss of hair on the scalp and rest of the body. In a few cases, hair loss is accompanied by the appearance of keratotic papules on the body. It is inherited in an autosomal recessive manner. Sequence variants in the HR (hairless) gene are responsible for this hair abnormality. Here, we present nine consanguineous families and one nonconsanguineous family with clinical manifestations of APL. Whole exome followed by Sanger sequencing and/or direct Sanger sequencing was performed to identify pathogenic variants. The study revealed seven novel pathogenic variants c.794del;p.(Pro265Argfs*98), c.2921-2936del;p.(Tyr974Leufs*16), c.2889C>A;p.(Cys963*), c.2689C>T;p.(Gln897*), c.3186&#95;3187dup;p.(Gln1063Profs*43), c.560dup;p.(Tyr188Ilefs*131), c.2203+5G>C, c.2776+5G>A, and the previously reported variant c.1837C>T;p.(Arg613*) in HR in these families. The study not only expands the mutational spectrum in the HR gene but also highlights the unusual phenotypic findings and will facilitate genetic counseling of families with members showing various types of hair loss disorders in the local population., (© 2024 Japanese Dermatological Association.)

Introduction: Gorlin syndrome is a rare, autosomal dominant multi-systemic disorder with a predisposition to the development of cancers such as medulloblastoma and nevoid basal cell carcinoma. Heterozygous pathogenic variants in PTCH1 are responsible for 90% of Gorlin syndrome cases. Pathogenic variants in PTCH1 cause overstimulation of the sonic hedgehog signaling pathway, which plays a role in the development of embryonic structures and tumorigenesis. Clinical major and minor diagnostic criteria for Gorlin syndrome have been determined. Odontogenic keratocyst (OKC) is the most common reason for medical admission in Gorlin syndrome. In this article, it is aimed to draw attention to the fact that patients with Gorlin syndrome are not very rare in our country and the variability in phenotypic and dysmorphic findings may be a clue for the diagnosis., Methods: Exome sequencing was performed on the Illumina NextSeq550 System platform by using the Ion Ampliseq exome RDY kit for Illumina. Sanger sequencing was performed accordingly for the other affected individuals in both families., Results: In this study, the clinical and molecular findings of 9 Gorlin syndrome patients from three unrelated families are presented. Macrocephaly, calcification of falx cerebri, palmar-plantar pits, rib anomalies, and OKC were detected in decreasing order in more than half of the patients. A novel heterozygous frameshift PTCH1 variant in family 1, a nonsense previously reported PTCH1 variant in family 2, and a novel heterozygous splice-site PTCH1 variant in family 3 were detected., Conclusion: Gorlin syndrome should be kept in mind in patients presenting with macrocephaly, palmoplantar pits, and OKC history. Careful examination of all family members is essential in the timely diagnosis of other affected individuals with minor phenotypic findings., Competing Interests: The authors declare no conflict of interest., (© 2024 S. Karger AG, Basel.)

Long-standing overt ventriculomegaly in adults (LOVA) is a kind of chronic hydrocephalus that has been reported to have started in infancy and is characterized by severe ventriculomegaly and macrocephaly. It often manifests clinically in later adulthood. We describe the case of a 34-year-old male patient who had a history of chronic alcoholism and who had been complaining of headaches, disturbed gait, and frequent falls for three months when he arrived in a stupor at the emergency room. Massive ventriculomegaly with Evans' index of 0.40 was found during a head magnetic resonance imaging (MRI). The MRI results were more severe than the clinical manifestations. He was diagnosed with LOVA and treated with conservative hyperosmolar drugs, neuroprotective agents, and intravenous (IV) thiamine. The patient was discharged and consented to follow-up after a hospital stay of seven days., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kadam et al.)

Background: Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians' understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference., Methods: Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed., Results: In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2., Limitations: The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians., Conclusion: Some ADOS items may better capture the signs that are most associated with clinicians' implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments., (© 2024. The Author(s).)