Mild Global Developmental Delay Research Articles

A nutritional Vitamin B12 deficiency (infantile tremor syndrome) presenting as hemiconvulsion hemiplegia epilepsy syndrome

Hemiplegia Hemiconvulsion Epilepsy syndrome (HHE syndrome) is a condition characterized by the acute onset of unilateral seizures, which progress to cortical atrophy, hemiplegia and later develop epilepsy over weeks to years. Various aetiologies include infectious causes, especially meningitis, encephalitis, trauma, vascular insults, and sometimes idiopathic. Here, we present a 13-month-old female child, first in birth order, born to a non-consanguineous marriage, who presented with mild global developmental delay with acute onset right focal seizures followed by right-sided weakness and drug-resistant epilepsy. The child was found to have clinical and biochemical features of vitamin B12 deficiency with right-sided weakness. MRI of the brain initially showed edema of the left cerebral hemisphere and later atrophy on the left side. The electroencephalogram showed low voltage activity over the left cerebral hemisphere. Post-treatment with cobalamin, improvement in development was noted, with partial improvement in weakness and persistent epilepsy. In the current report, we highlight Hemiplegia Hemiconvulsion Epilepsy (HHE) syndrome on the background of nutritional vitamin B12 deficiency.

Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n ​= ​1) or G239S variant (n ​= ​2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 ​mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.

Severe KIDAR syndrome caused by deletion in the AP1B1 gene: Report of a teenage patient and systematic review of the literature

Autosomal recessive keratitis-ichthyosis-deafness syndrome (KIDAR MIM #242150) is a very rare disorder caused by pathogenic loss-of-function variants in the AP1B1 gene. So far, nine patients have been reported in the literature and more clinical descriptions are essential to further delineate the phenotype of KIDAR. Here we report a new patient with KIDAR and compare the clinical findings with those from the other published cases with molecular confirmation.We describe a 14-year-old male born to non-consanguineous parents with unremarkable family history. The patient had fetal ascites, neonatal pancreatic insufficiency with consequent failure to thrive, feeding difficulties, recurrent infections and sepsis. The skin examination was remarkable for an ichthyosis with conspicuous palmoplantar keratoderma, sparse and brittle hair with alopecia on the vertex and slight bilateral ectropion. He had short stature, thin build, frontal bossing, small teeth and prominent abdomen. Additional features were congenital profound bilateral sensorineural deafness, photosensitivity and photophobia. Mild global developmental delay was noted. Persistent mild anemia, neutropenia, thrombocytopenia, and low serum copper, ceruloplasmin and growth hormone were also present. Brain magnetic resonance imaging (MRI) showed cerebral atrophy and thin corpus callosum. Genetic testing revealed a homozygous deletion in the AP1B1 gene, possibly including the same exons as a previously reported deletion.Comparing the phenotypes of all reported individuals, they are highly concordant and major features are enteropathy with feeding difficulties, failure to thrive, ichthyosis, palmoplantar keratoderma, sensorineural deafness and sparse and brittle hair. Here we report other features present in more than one patient that could be part of the phenotypic spectrum and suggest copy number variation analysis to be performed alongside sequencing of the AP1B1 gene in case of suspicion.

Targeted sequencing and clinical strategies in children with autism spectrum disorder: A cohort study.

Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with genetic and clinical heterogeneity. Owing to the advancement of sequencing technologies, an increasing number of ASD-related genes have been reported. We designed a targeted sequencing panel (TSP) for ASD based on next-generation sequencing (NGS) to provide clinical strategies for genetic testing of ASD and its subgroups. Methods: TSP comprised 568 ASD-related genes and analyzed both single nucleotide variations (SNVs) and copy number variations (CNVs). The Autism Diagnostic Observation Schedule (ADOS) and the Griffiths Mental Development Scales (GMDS) were performed with the consent of ASD parents. Additional medical information of the selected cases was recorded. Results: A total of 160 ASD children were enrolled in the cohort (male to female ratio 3.6:1). The total detection yield was 51.3% for TSP (82/160), among which SNVs and CNVs accounted for 45.6% (73/160) and 8.1% (13/160), respectively, with 4 children having both SNVs and CNV variants (2.5%). The detection rate of disease-associated variants in females (71.4%) was significantly higher than that in males (45.6%, p = 0.007). Pathogenic and likely pathogenic variants were detected in 16.9% (27/160) of the cases. SHANK3, KMT2A, and DLGAP2 were the most frequent variants among these patients. Eleven children had de novo SNVs, 2 of whom had de novo ASXL3 variants with mild global developmental delay (DD) and minor dysmorphic facial features besides autistic symptoms. Seventy-one children completed both ADOS and GMDS, of whom 51 had DD/intellectual disability (ID). In this subgroup of ASD children with DD/ID, we found that children with genetic abnormalities had lower language competence than those without positive genetic findings (p = 0.028). There was no correlation between the severity of ASD and positive genetic findings. Conclusion: Our study revealed the potential of TSP, with lower cost and more efficient genetic diagnosis. We recommended that ASD children with DD or ID, especially those with lower language competence, undergo genetic testing. More precise clinical phenotypes may help in the decision-making of patients with genetic testing.

Cerebral venous thrombosis and B12 deficiency

Infants with prematurity and necrotizing enterocolitis (NEC) are at increased risk for short bowel syndrome and subsequent nutritional deficiencies. In particular, ileal resection is associated with vitamin B12 malabsorption, which interferes with normal myelination and homocysteine metabolism.1, 2 Vitamin B12 deficiency is associated with neurodevelopmental delay as well as hyperhomocysteinemia, which increases the risk for venous thrombosis.2, 3 This eight-year-old boy presented with severe headache, dehydration, and lethargy. He developed acute onset severe frontal headache followed by decreased oral intake, decreased urine output, and recurrent vomiting. The headache was dull and radiating to the back of his head. At the same time, he appeared to be sleepy and less active. These symptoms lasted for two to three days before he was brought to the primary doctor's office and then referred to the emergency department. On assessment, he was tired-looking and exhibited mild microcephaly, but his neurological examination was normal, as was an examination by an ophthalmologist. He experienced mild global developmental delay. He was born at 25 weeks gestational age and had a prolonged stay in the neonatal intensive care unit, complicated by NEC and a hemicolectomy with ileostomy and removal of ileocecal valve. He had low normal levels of B12 for several years prior to presentation and was not treated (151 pg/ml after surgery [normal 160-950]). Brain magnetic resonance imaging and magnetic resonance venography (MRV) showed filling defects in the inferior sagittal, straight, torcula, and proximal transverse sinuses consistent with cerebral venous sinus thrombosis (CVST) with no evidence of acute infarction (Figure 1). Dehydration was initially considered to be the cause. Enoxaparin sodium was started at 1 mg/kg every 12 h with the goal of anti-Xa level between 0.5 and 1.0 U/ml. The hypercoagulation evaluation was normal. The B12 level was 86 pg/ml. His hematocrit was 33.3, and his mean corpuscular volume (MCV) was 87.4. He was not treated at that time. He was discharged within a week after the repeat imaging remained stable with the goal to continue enoxaparin sodium for three months. After three months, he again developed headache and lethargy, and MRV showed a new thrombus. Enoxaparin was switched to warfarin. After a year of warfarin, the clot resolved but he still had headaches. Two B12 levels were obtained, both below 200. His anemia worsened (hematocrit 24.7) and his MCV increased to 96.9. The homocysteine level was 184 μmol/L (normal <11.4). At this point, he began B12 injections (1000 mcg daily for one week followed by monthly and then quarterly injections thereafter). His B12 levels normalized and remained normal throughout his course. The warfarin was discontinued and thrombus has not recurred. Our patient had a difficult-to-treat CVST secondary to a condition predisposing to nutritional deficiency. His chronic B12 deficiency was overlooked by his treating physicians until he presented with a profound deficiency with megaloblastic anemia. The association between B12 deficiency and CVST has been described in children with nutritional deficiency and megaloblastic anemia.4 Previous authors suggested that testing for hyperhomocysteinemia and with B12 supplementation should be considered in pediatric patients with CVST.5 The diagnosis becomes even more crucial in patients with conditions known that promote nutritional deficiencies, such as a history of NEC and ileal surgery. In such children, early recognition of vitamin B12 deficiency and timely vitamin supplementation may prevent the occurrence of CVST as well as other manifestations of B12 deficiency, such as developmental delay.6, 7 In this patient, the B12 deficiency was chronic. While it is difficult to prove that the deficiency caused the CVST, it likley played a substantial role. Hyperhomocysteinemia can damage the vascular endothelium, predisposing to thrombus formation.8, 9 Consequently, vitamin B12 deficiency is a potential risk factor in children with CVST. Fatemeh Mohammadpour Touserkani: Conceptualization; supervision; writing – original draft; writing – review and editing. Theodora Andriotis: Conceptualization; investigation; writing – original draft; writing – review and editing. Yaoping Zhang: Conceptualization; supervision; writing – original draft; writing – review and editing. Steven Pavlakis: Conceptualization; supervision; writing – original draft; writing – review and editing. We would like to thank the patient's parents for their consent for this publication. The authors declare no conflict of interest.

Publicly funded exome sequencing for outpatients with neurodevelopmental disorders demonstrates a high rate of unexpected findings impacting medical management

PurposeExome sequencing (ES) is a powerful tool that facilitates the diagnosis of patients with rare Mendelian syndromes. In 2018 the Israeli Ministry of Health initiated a national pilot program that funds ES for outpatients with global developmental delay (GDD). Here, we describe the 3-year impact of this program on patient care in a single tertiary hospital. MethodsFrom 2018 to 2020, trio ES was performed on 170 participants fulfilling Israeli Ministry of Health criteria: (1) moderate to severe GDD and (2) mild GDD with epilepsy or a major congenital anomaly. We retrospectively analyzed this cohort. ResultsA diagnosis was achieved in 74 individuals (43%). There were 82 clinically significant variants, the majority being novel. Consanguinity was reported in 22% and was not associated with a higher diagnostic rate. The presence of autism spectrum was associated with a lower diagnostic rate of 8/33 (24%). Autosomal dominant inheritance was identified in 14% of participants, and the parental phenotype ranged between fully affected and asymptomatic. Among the diagnosed participants, 16% had an unexpected diagnosis that did not fit the typical clinical presentation. In 9%, the diagnosis changed short-term active clinical management, in 19%, the surveillance recommendations, and in 23%, the family-focused outcomes. ConclusionThe introduction of a national program that funds ES for GDD has transformed patient care, leading to a significant effect on medical management and treatment. The high rate of an unexpected inheritance mode and variable phenotypes emphasizes the diagnostic complexity of neurodevelopmental disorders and the strength of a non-targeted approach.

Kagami–Ogata syndrome: a case report

BackgroundKagami–Ogata syndrome is a rare genetic imprinting disorder involving the 14q32.2 genomic location of chromosome 14. The estimated incidence is less than 1 per 1 million. Here we report a male neonate with Kagami–Ogata syndrome presenting with severe respiratory distress requiring mechanical ventilation since birth.Case presentationA Sri Lankan male neonate born at term via caesarean section to a mother with type 1 diabetes mellitus and hypothyroidism developed respiratory distress immediately after birth. On examination, the baby had facial dysmorphism with a hirsute forehead, full cheeks, flat nasal bridge, elongated protruding philtrum, and micrognathia. His chest was small and bell shaped, and he had severe intercostal and subcostal recessions. His abdominal wall was lax and thin, with evidence of divarication of the recti. Bowel peristalsis was easily visible through the abdominal wall. The chest x-ray showed narrowing of the rib cage with crowding of the ribs in a “coat-hanger” appearance. The coat-hanger angle was 32°, and the mid-to-widest thoracic diameter was 68%. On the basis of facial dysmorphism, chest and anterior abdominal wall abnormalities, coat-hanger appearance of the rib cage, increased coat-hanger angle, and reduced mid-to-widest thoracic diameter, a clinical diagnosis of Kagami–Ogata syndrome was made. Owing to severe respiratory distress, the baby required intubation and ventilation immediately after birth. He was ventilator-dependent for 3 weeks; however, he was successfully weaned off the ventilator on day 22 after several failed extubation attempts. At 3-month follow-up, he had generalized hypotonia and mild global developmental delay. His developmental age corresponded to 2 months.ConclusionsWe report a patient with Kagami–Ogata syndrome presenting with respiratory distress immediately after birth. This case report highlights the importance of being aware of this rare condition, which could present as severe respiratory distress in term and preterm newborns. A positive diagnosis could avoid unnecessary treatment and aid in accurate prognostication.

EP296: Familial MECP2 variants: a report of 4 affected families highlighting the variable phenotypic spectrum and implications for genetic counseling

Pathogenic variants in MECP2 cause a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT; 312750). Although historically this was considered an X-linked dominant diagnosis with male lethality, it is now known that males can also be affected, with a disease spectrum ranging from severe neonatal encephalopathy to intellectual disability (ID). Other features commonly seen in RTT are inconsistently present in males. A qualified genotype-phenotype correlation exists, with variants that are known to cause RTT in females most often leading to more severe phenotypes in males. Additionally, whereas pathogenic MECP2 variants identified in affected females with classic and atypical RTT are most often de novo variants, pathogenic variants in males may be either de novo or maternally inherited. Here we report 4 novel families with pathogenic MECP2 variants. In all 4 families, the affected probands were male and maternal inheritance was identified. Family 1: The proband is a now 8-year-old male with mild global developmental delay, epilepsy, ataxia, and hypotonia. He also has significant anxiety. Epilepsy gene panel identified a hemizygous pathogenic variant in MECP2 (c.491C>T; p.Ala140Val); targeted testing confirmed maternal inheritance. His mother has no significant medical issues or learning issues, but endorses a history of anxiety. He has four clinically unaffected siblings; one brother has been tested and is negative. His other brother and sisters have not been tested. Family 2: The proband is a now 47-year-old male with mild-moderate intellectual disability. Genetic testing was initiated after MRI performed in the context an episode of confusion and shaking concerning for a panic attack revealed signal abnormalities in the bilateral cerebral peduncles possibly concerning for Fragile X Associated Tremor Ataxia Syndrome (FXTAS). He also experienced a motor regression and onset of dystonia after an episode of rhabdomyolysis in his mid 40’s and has not returned to baseline. Trio exome sequencing identified a maternally inherited hemizygous pathogenic variant (c.499C>T; p.Arg167Trp) in MECP2. Cascade testing identified that his sister and niece also both carry the familial MECP2 variant. His sister has a history of learning difficulties, significant anxiety, obsessive compulsive disorder, and has developed progressive spasticity with hyperreflexia and sustained clonus over time. His niece also has anxiety, obsessive compulsive disorder, and bipolar disorder. Family 3: The proband is a now 37-year-old male with mild intellectual disability and autism spectrum disorder. He also has a history of anxiety and depression. Trio exome sequencing identified a maternally inherited hemizygous pathogenic variant (c. 1136_1151del16; p.Pro379HfsX25) in MECP2. Testing was initiated after the onset of abnormal movements in his thirties suggestive of dystonia. Exam was notable for kyphosis and shuffling gait. His mother reports a history of anxiety, but no learning or cognitive concerns and no other neurologic symptoms. He has one clinically unaffected sister who has not yet been tested. Exome sequencing also identified a de novo, heterozygous c.1672C>T (p.Arg558Cys) variant of uncertain significance in ALDH18A1, though it is unclear whether or not this is contributing to his phenotype. Family 4: The proband is a now 8-year-old male who initially presented for evaluation due to concern for global developmental delay, hypotonia, and macrocephaly. Family history was unremarkable. MRI identified prominent perivascular spaces. Trio exome sequencing identified a maternally inherited likely pathogenic hemizygous variant (c.1244delC; p.Pro415LeufsX6) in MECP2. The proband’s younger brother subsequently presented with expressive language delay and was also macrocephalic. Targeted testing confirmed the presence of the familial MECP2 variant. These 4 familial reports of pathogenic MECP2 variants add to the data provided by previous publications describing the phenotypic spectrum in affected males and supporting that many of the variants may be maternally inherited. Affected male probands in all cases presented with developmental delay and/or intellectual disability. Only 1/4 probands had epilepsy. Anxiety was present in 3/4. Cascade testing identified carrier female relatives with a prominent neuropsychiatric phenotype in one family. Anxiety was also reported in the mothers of two other families, without any other cognitive or neurologic features. Although two families harbored pathogenic missense variants previously known to be associated with an X-linked intellectual disability phenotype, two families with mildly affected male probands and unaffected female carrier mothers had novel, predicted loss of function variants that would have been expected to result in a RTT phenotype. These families highlight the clinical variability that can be seen with pathogenic MECP2 variants and challenge reported genotype-phenotype correlations, providing important information for genetic counseling.

Harlequin Syndrome, Apnea, and Acute on Chronic Hemiparesis: An Atypical Pediatric Case of Chiari I With Holocord Syringohydromyelia

A four-year-old, right-handed, term female, with mild global developmental delay, presented to the emergency department for evaluation of progressive right hemiparesis. Her development was significant for walking at 18 months and expressive speech delay. At age 3.5 years, she was diagnosed with Harlequin syndrome (Fig 1) after multiple episodes of left hemifacial flushing with physical exertion. Concurrently, she began dragging her right leg and was diagnosed with hemiplegic cerebral palsy by an outside hospital.

Heterogeneous Clinical Characteristics of Allan-Herndon-Dudley Syndrome with SLC16A2 Mutations

Purpose: The purpose of this study was to expand our understanding of phenotypic and genetic variation in Allan-Herndon-Dudley syndrome (AHDS), which is a rare X-linked mental retardation syndrome characterized by hypotonia, generalized spasticity, and moderate-to-severe psychomotor retardation. AHDS is caused by a mutation of solute carrier family 16 member 2 (SLC16A2), which encodes monocarboxylate transporter 8 (MCT8), the transporter of triiodothyronine (T3) into neurons. Methods: We enrolled nine patients with AHDS from unrelated families, except for two patients who were cousins, through a retrospective chart review. Clinical features, brain imaging, electroencephalograms, thyroid hormone profiles, and genetic data were reviewed retrospectively and compared with previously reported cases. Results: We found three novel and five previously reported pathogenic variants in nine patients from eight families. All patients presented with hypotonia, spasticity, severe developmental delay, and elevated serum T3 levels. Cataplexy, which is a previously unreported phenotype, was found in two patients with the same mutation. In our cohort, seizures were uncommon (n=1) but intractable. Conclusion: This study broadens the known phenotypic variations of AHDS, ranging from relatively mild global developmental delay to a severe form of encephalopathy with hypotonia, spasticity, and no acquisition of independent sitting. The syndromic classification or genetic etiology of global developmental delay is extremely heterogeneous; therefore, early clinical suspicion is challenging for clinicians. However, severe mental retardation with hypotonia, spasticity, and elevated serum T3 levels in male patients is a highly suspicious clinical clue for the early diagnosis of AHDS.

Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation.

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3′ end of the gene, confirming the genotype-phenotype correlation initially described.

Weiss-Kruszka Syndrome With Unreported Manifestations; Empty Sella Syndrome Associated With Growth Hormone Deficiency

Objective: Weiss-Kruszka syndrome (WSKA; MIM#618,619) is a rare, autosomal dominant disorder associated with zinc finger protein 462 (ZNF462) gene variation or deletion of 9q31.2 involving ZNF462 and various congenital anomalies. Its specific clinical findings are abnormal facial shape, prominent forehead, high arched eyebrow, ptosis, delayed development of motor and language and mild global developmental delay. The prevalence of WSKA is only 25 individuals from literatures. Brain lesions related to WSKA are known as ventriculomegaly and middle line brain abnormalities like corpus callosum hypoplasia in about 25 percent of the patients. However, there have not been reported a patient who has structural malformation of pituitary gland with endocrine dysfunction. Here, we present a Korean boy molecularly confirmed as WSKA, having newly clinical manifestation of primary empty sella syndrome(ESS) associated with growth hormone deficiency(GHD). Case Presentation: A 16-year-old boy visited to our hospital presented with severe short stature and delayed puberty. He also complained mild hypotonia, congenital both ptosis, mild intellectual disability. In the anterior pituitary combined test, GHD was diagnosed. In the brain magnetic resonance image, ESS was showed. With starting and continuing recombinant human growth hormone replacement therapy, to identify the underlying genetic cause, chromosomal microarray analysis and whole exome sequencing test were conducted. Finally, a heterozygous novel frameshift variant, c.4185del(p.Met1396Ter) in ZNF462 confirmed by Sanger sequencing, which had not been reported was identified Conclusions: This is the first case of WSKA of an Asian with novel pathogenic variant of ZNF462 and new clinical features including primary ESS associated with GHD. This case could contribute to diagnosis of this syndrome, identify clinical features and provided novel insight into studies for the role of ZNF462 gene.

Pediatric cerebellar malformations: magnetic resonance diagnostic merits and correlation with neurodevelopmental outcome

BackgroundIn spite of having many classifications for pediatric cerebellar malformations (PCMs), no broadly accepted classification is recommended. Associated neurodevelopmental outcomes in children with PCMs remain poorly defined. Neuroimaging is compulsory for the diagnosis of cerebellar malformation and their associated abnormalities. This article emphasizes on the clinical and radiological traits of PCMs. It proposes a radiological classification and a diagnostic approach and assesses whether specific neuroimaging features in patients with PCM correlate with their neurodevelopmental outcomes.ResultsFifty-eight pediatric patients were classified as follows: The majority of about 51 cases (88%) showed cerebellar hypoplasia and the remaining 7 cases (12%) showed cerebellar dysplasia. Twenty-six patients (45%) remained undiagnosed, while 32 patients (55%) were having a final diagnosis (24% Dandy-Walker malformation (DWM) (n = 14), 7% isolated vermian hypoplasia (n = 4), 7% congenital disorder of glycosylation (CDG) (n = 4), 5% congenital muscular dystrophy (n = 3), 5% congenital cytomegalovirus (CMV) infection (n = 30), 3% rhombencephalosynapsis (n = 2), 2% Lhermitte-Duclos syndrome (n = 1), and 2% DWM with Joubert syndrome (n = 1)). Overall, for the neurodevelopmental outcome, the majority of patients 90% (52/58) had a global developmental delay (GDD) which is a delay in two or more developmental domains. Both motor and language delay represented about 72% (37/58), intellectual disability was present in 59% (34/58), epilepsy in 53% (31/58), ataxic gait in 57% (33/58), attention deficit hyperactivity disorder (ADHD) in 19% (11/58), autism spectrum disorder (ASD) in 17% (10/58), nystagmus and tremors in 15% (9/58), and behavioral changes in 7% (6/58). Most of the children with cerebellar hypoplasia, about 93%, had GDD. Also, patients with PCH associated with a severe GDD, 75% had a language delay, 50% had intellectual and motor delay, and about 25% had epilepsy. However, we observed mild GDD in half of the vermian hypoplasia cases and half of them had a mild fine motor delay.ConclusionsMagnetic resonance imaging (MRI) of the pediatric brain provides key information to categorize and classify cerebellar malformations. A neurodevelopmental deficit is highly associated with different types of PCMs. Severe GDD was associated with cerebellar and brain stem involvement. However, children with vermis mal-development were likely to have mild GDD. Familiarity with their diagnostic criteria is mandatory for correct diagnosis and prognosis for patients.

Further delineation of putative ACTB loss-of-function variants: A 4-patient series.

ACTB encodes β‐cytoplasmic actin, an essential component of the cytoskeleton. Based on chromosome 7p22.1 deletions that include the ACTB locus and on rare truncating ACTB variants, a phenotype resulting from ACTB haploinsufficiency was recently proposed. We report putative ACTB loss‐of‐function variants in four patients. To the best of our knowledge, we report the first 7p22.1 microdeletion confined to ACTB and the second ACTB frameshifting mutation that predicts mRNA decay. A de‐novo ACTB p.(Gly302Ala) mutation affects β‐cytoplasmic actin distribution. All four patients share a facial gestalt that is distinct from that of individuals with dominant‐negative ACTB variants in Baraitser‐Winter cerebrofrontofacial syndrome. Two of our patients had strikingly thin and sparse scalp hair. One patient had sagittal craniosynostosis and hypospadias. All three affected male children have attention deficits and mild global developmental delay. Mild intellectual disability was present in only one patient. Heterozygous ACTB deletion can allow for normal psychomotor function.

SAT-296 Congenital Adrenal Hyperplasia Presenting as Central Precocious Puberty

Background: Sometimes peripheral precocious puberty (PPP) is the underlying cause of central precocious puberty (CPP) and is called as secondary CPP. In most of the secondary CPP, the role of the PPP is evident at diagnosis of CPP. Here we report a case of secondary CPP who was initially misdiagnosed as idiopathic CPP. Case presentation A-6.25-years-old boy, born of a third degree consanguineous consummation, presented with appearance of pubic hair and enlargement of phallus since the age of 4 years. He has history of mild global developmental delay, predominantly affecting language milestones. There was no family history of early puberty, sibling deaths or ambiguous genitalia. His height was 113 cm (-0.54 SDS ) and mid-parental height was 176.5 (+0.31 SD), Sexual maturity rating was P3, G3 (stretched phallic length: 6 cm) and bilateral testes measuring 5 cc each. He had multiple large café-au-lait spots over the lower extremities with irregular borders. Bone age was 9.5 years. Serum testosterone was elevated (190.1 ng/dl) with LH of 0.31 mIU/ml and FSH of 1.25 mIU/ml. Thyroid function was normal (TSH: 1.11 µIU/ml, FT4: 1.56 ng/dl). Leuprolide stimulation was done which suggested central precocious puberty (peak LH: 10.61mIU/ml, peak FSH: 3.75 mIU/ml). MRI of the pituitary hypothalamic area was normal. He was diagnosed to have idiopathic CPP and was initiated on leuprodile depot preparation 3.75 mg intramuscularly once a month. After 6 months, he had grown 5 cm (and basal serum testosterone was still elevated (185.3 ng/dl), LH: <0.01 mIU/ml). Adequate LH suppression was also confirmed with suppressed LH (peak LH: 0.95 mIU/ml) after leuprolide depot stimulation. Hence, he was suspected to have secondary CPP and was evaluated for the cause. Serum 8:00 am cortisol was 7.48 µg/dl and β-hCG was undetectable. Basal 17OHP (16.79 ng/ml) and ACTH stimulated 17OHP (54 ng/ml) were elevated. Hence, a diagnosis of simple virilising CAH with secondary CPP was done. Patient was started on oral hydrocortisone (10 mg/m2/day) and shifted to leuprodile depot preparation 11.25 mg Q12 weekly. After 3 months basal serum testosterone was 45 ng/ml and LH was < 0.01 mIU/ml. Conclusion: In a patient with hormonal profile suggestive of CPP, a disproportionately smaller testes for a given serum testosterone should suggest a secondary cause for CPP. In patients treated with GnRH agonist for CPP, persistent growth acceleration and/or persistently elevated sex steroid but well-suppressed LH should also suggest a secondary cause for CPP.

New ocular finding in Baraitser-Winter syndrome (BWS)

Baraitser-Winter syndrome was first described as a syndrome of iris coloboma, ptosis, hypertelorism, and mental retardation (Baraitser and Winter 1988; Baraitser, 2016). The phenotypic spectrum has since broadened to include other facial dysmorphic features, deafness, microcephaly, lissencephaly, and CNS findings (Baraitser and Winter 1988; Ganesh et al., 2005; Henedy et al., 2010; Verloes et al., 2015). The syndrome is due to pathogenic variants on either ACTB or ACTG1 genes (Di Donato et al., 2014; Rivière et al., 2012). There is still discussion which gene variant produces a more severe phenotype (Di Donato et al., 2016; Di Donato et al., 2014; Verloes et al., 2015). We report a 3-year-old girl with short stature, mild global developmental delay, minor brain anomalies and few dysmorphic features including unusual stroma of the irises and unreported corectopia. Exome sequencing reported a de novo likely pathogenic variant on the ACTB gene. The present report adds a new ocular finding to the phenotypic spectrum.

Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation

Hypochondroplasia (HCH), an autosomal dominant skeletal dysplasia caused by mutations in the FGFR3 gene, has not been commonly associated with neurological problems. Temporal lobe dysgenesis associated with epilepsy was recently described in single patients. In this retrospective study, we assessed neurological and neuroimaging aspects of 13 FGFR3 (N540K) mutation verified HCH patients in Finland. Eight patients had neurocognitive difficulties, ranging from specific learning disorder (2/13) to mild intellectual disability (5/13) or global developmental delay (1/13). Six of 13 patients had a history of seizures or epilepsy. Eight patients had undergone MRI. They all had structural abnormalities consistent with temporal lobe dysgenesis. Six patients had peritrigonal white matter reduction, and 4 had abnormally shaped lateral ventricles. We recommend a close follow-up of development in patients with HCH and a low threshold for neuroimaging.

22q13.32 Deletion and Duplication and Inversion in the Same Family: A Rare Occurrence

Chromosome 22q13.3 deletion syndrome is a well-recognized cause of global developmental delay, while duplication of the same chromosome is a rare occurrence. The presence of both abnormalities in the same family has never been reported, to our knowledge. We report a rare occurrence of 22q13.3 duplication and 22q13.3 deletion in siblings, as a consequence of a mother's inversion on her 22nd chromosome (p13;q13.32). A 6 year old male was noted in infancy to have mild global developmental delay without dysmorphic features. His genetic testing revealed he had 22q13.3 duplication to the terminus. His 4 year old brother was noted in early infancy to have severe global developmental delay and dysmorphic features related to 22q13.3 deletion to the terminus. Their mother had a long inversion on her 22nd chromosome. Genetic tests for their father and eldest brother were unremarkable. The mother's inversion may rearrange to form 22q duplication or deletion when passed on to children. The chance of a child born with a chromosome imbalance is as high as 50%.

An Emerging 1q21.1 Deletion-Associated Neurodevelopmental Phenotype

In this study, we describe the neurodevelopmental and epileptic phenotypes in a family with an inherited 1q21.1 deletion. During the pregnancy with the proband, increased nuchal translucency and oligohydramnion were detected. The proband showed mild global developmental delay and ataxic gait. Seizures started in the proband at the age of 2 years and manifested as generalized tonic-clonic seizures, atypical absence seizures, head drops, and drop attacks with no abnormal findings on interictal electroencephalogram. We performed an Agilent Human Genome CGH (comparative genomic hybridization) Microarray 105A, and a microdeletion on chromosome 1q21.1 was identified in both the patient and his asymptomatic father. This deletion encompasses 1.65 Mb and is larger than the reported recurrent class I deletions in this region. Cryptic cytogenetic abnormalities should be considered in patients with neurodevelopmental problems and atypical presentation of epilepsy with a normal electroencephalography (EEG).

What’s Your Diagnosis?

A 14-month-old girl presented for further evaluation for glaucoma with a history of esotropia and concern for corneal clouding first seen by her mother at 9 months of age without associated epiphora or photophobia. At 11 months of age, an examination under anesthesia recorded the presence of suspected epithelial edema with bilateral borderline elevated intraocular pressures. After removal of the temporal corneal epithelium, strikingly clear visualization of the filtration angle was present. Bilateral goniotomies were then performed. One month postoperatively, the examination under anesthesia was repeated and moderately improved intraocular pressures were measured and persistent epithelial opacification was present. She had just begun standing and her pediatrician had noted mild global developmental delay. Her parents are both of Ashkenazim ancestry. On examination, she possessed mild coarse facial features and generalized hypotonia without hepatosplenomegaly or skin abnormalities. She fixed and followed well without nystagmus. Her corneas were diffusely cloudy and thickened bilaterally (Figure). Corneal diameter measurements, intraocular pressures, gonioscopic findings, and lenses were normal. The fundi were normal, without evidence of retinal vessel attenuation or optic atrophy. Conjunctival and corneal epithelial biopsies were performed. Electron microscopic analysis revealed lysosomal membrane-bound intracytoplasmic lamellar inclusion bodies that confirmed the suspected diagnosis.