Compound heterozygous ADAMTS9 variants in Joubert syndrome-related disorders without renal manifestation.

BACKGROUND: Ciliopathies are the outcomes of defects of primary cilia structures and functions which cause multisystemic developmental disorders, such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, Joubert syndrome (JS), and JS-related disorders (JSRD) with additional organ involvement including oral-facial-digital syndrome and so on. They often share common and unexpected phenotypic features. CASE PRESENTATION: We report a 4-year-old-boy case with compound heterozygous variants of ADAMTS9. Unlike the cases with ADAMTS9 variants in the previous report, which identified that homozygous variants of ADAMTS9 were responsible for nephronophthisis-related ciliopathies in two cases, the current case did not have nephronophthisis nor renal dysfunction, and his clinical features, such as oculomotor apraxia, hypotonia, developmental delay, bifid tongue, and mild hypoplasia of cerebellar vermis indicated JSRD. CONCLUSIONS: The case suggested a possible association between the clinical presentation of JSRD and ADAMTS9-related disease, and it shows a wide spectrum of ADAMTS9 phenotype.

A case of meningitis due to Achromobacter xylosoxidans in a child with a polymalformative syndrome: a case report.

Achromobacter xylosoxidans (AX), also called alcaligenes xylosoxidans, is an aerobic, non-fermenting mobile, gram-negative bacillus which was first isolated in an otorrhea samples in 1971. Infections with these species are quite rare and have often been described in immunocompromised and in premature infants. However, very few cases of meningitis related to AX have been reported in the literature. The authors report a new case of meningitis due to AX in a 45-day-old female infant with polymarformative syndrome meningitis was confirmed by a cyto-biochemical analysis and culture of the cerebrospinal fluid and was treated by antibiotherapy. Hydrocephalus was managed initially with external ventricular drainage followed by a ventriculoperitoneal shunt after rigorous cerebrospinal fluid (CSF) sterilization, with good clinical and radiological outcomes. The prompt and adequate antibiotic adjustment following bacterial isolation has been shown to rapidly modify the clinical outcomes.

Multicorrection Goldenhar syndrome (facio-auriculo-vertebral dysplasia): a rare follow-up case of 12-year-old female.

The MSX homeobox genes cause Goldenhar syndrome (GHS) or facio-auriculo-vertebral dysplasia, a rare developmental defect. Its exact etiology is still unknown. Its incidence lies between 1: 3500 and 1: 5600. In 85% of the cases, the unilateral face is affected. Typical clinical findings in a classic GHS include eye disorders, ear irregularities (with or without hearing loss), facial impairments, dental and oral ailments, cardiac syndromes, central nervous system (CNS) involvement, trachea and lung malformations, kidney and gastrointestinal defects, and skeletal alterations. This case report presents a follow-up case of Goldenhar Syndrome in a 12-year-old female, with no relevant family history, diagnosed with anotia on the left side, cyanosis, and facial asymmetry at birth. She presented with moderate growth failure, bilateral sclerosing mastoiditis and kyphoscoliosis. She underwent posterior scoliosis correction posterior instrumented fusion from D1 to D11.

Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3.

KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of -1 SDs to -2 SDs were noted in about half of the patients; only two patients presented with short stature below -3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.

A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria.

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses.

Cardiac anomalies associated with Escobar syndrome: A case report and a review of the literature.

RATIONALE: Escobar syndrome (ES) is an autosomal recessive disorder. It is highly characterized by facial abnormalities, congenital diaphragmatic muscle weakness, myasthenic-like features, and skin pterygiums on multiple body legions. ES is a rare condition associated with many external and internal abnormalities. The internal malformations described in ES affect many organs including the heart, lungs, esophagus, liver, spleen, and intestine. The purpose of this paper is to explore the cardiac manifestations associated with ES. PATIENT CONCERNS: A 3.5-year-old girl, who was born for double first cousins, was admitted to the hospital for neuromuscular evaluation of multiple congenital contractures. DIAGNOSIS: The girl was diagnosed with ES and isolated dextrocardia which is a rare cardiac manifestation. However, to the best of our knowledge, no similar cases have been reported to date, and this case is thus believed to be very rare. INTERVENTIONS: The patient underwent an operative intervention to correct the bilateral fixed flexion deformity at her knees which was related to the posterior bilateral fibrotic bands/pterygia. OUTCOMES: Post-operatively, complete knee extension was obtained, the patient was fitted with a cast and extension night splint. She was discharged alive and had no complications. The patient was followed regularly in the orthopedic clinic and had periodic physiotherapy sessions. CONCLUSIONS: ES and isolated dextrocardia concurrence in the presented case resulted from different pathogenic mechanisms. Our findings suggest that ES might be caused by dysfunction in the acetylcholine receptor throughout fetal life, which may have affected muscle strength and movement. Other cardiac conditions include hypoplastic left-sided heart, Hypertrophic cardiomyopathy, patent ductus arteriosus, and heterotaxia.

Detailed clinical and radiological features of the first patient with Elsahy-Waters syndrome in East Asia.

Elsahy-Waters syndrome (EWS; OMIM#211380) is a rare autosomal recessive disorder that is caused by loss-of-function variants in CDH11, which encodes cadherin 11. EWS is characterized by brachycephaly, midface hypoplasia, characteristic craniofacial morphology, cervical fusion, cutaneous syndactyly in 2-3 digits, genitourinary anomalies, and intellectual disability. To the best of our knowledge, there have been only six patients of molecularly confirmed EWS. We report the first patient of EWS in East Asia in a Japanese man with a novel splice site homozygous variant of CDH11. We reviewed the clinical and molecular findings in previously reported individuals and the present patient. In addition to the previously reported clinical features of EWS, the present patient had unreported findings of atlantoaxial instability due to posterior displacement of dens, thoracic fusion, thoracic butterfly vertebra, sacralization of the lumbar vertebra (L5), and multiple perineural cysts. The spinal findings in this patient could represent a new spectrum of skeletal phenotypes of EWS. It remains to be clarified whether the multiple perineural cysts in the patient were associated with EWS or coincidental. The current observation might contribute to an expanded understanding of the clinical consequences of loss-of-function of cadherin 11.

5q11.2 deletion syndrome revisited-Further narrowing of the smallest region of overlap for the main clinical characteristics of the syndrome.

Microdeletions at 5q11.2 are rare. Subjects show a phenotypic spectrum that overlaps CHARGE syndrome and 22q11.2 deletion syndrome. A growing number of subjects present with learning difficulty and/or intellectual disability, immune deficiency, congenital heart malformation, and dysmorphism. DHX29 and IL6ST have been proposed as candidate genes for the development of the major clinical manifestations. We present a new case and narrow down the shortest region of overlap to evaluate possible candidate genes. Our case does not present developmental delay or immune deficiency indicating a reduced penetrance for some of the main clinical manifestations. The shortest region of overlap between subjects with deletions at 5q11.2 is approximately 450 kb (position 54.3-54.7 Mb). The narrowed region comprises 10 protein coding genes, including DHX29. DHX29 is a strong candidate gene for the main features of 5q11.2-microdeletion syndrome; however, our findings suggest a joined impact of several genes as the cause of the syndrome.

The MED13L haploinsufficiency syndrome associated with de novo nonsense variant (P.GLN1981*).

The Mediator complex subunit 13-like is a part of the large Mediator complex. Recently, a large number of patients were diagnosed with mutations in this gene, which makes it one of the most frequent causes of syndromic intellectual disability. In this work, we report a patient with a novel de novo likely pathogenic variant c.5941C>T, p.(Gln1981*) in the MED13L gene with severe intellectual disability and facial dysmorphism. Uncommon findings like lack of speech, strabismus and self-destructive behaviour present in our patient allowed us to further define the phenotypic spectrum of mental retardation and distinctive facial features with or without cardiac defects syndrome.

Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus.

Filippi syndrome (MIM #272440), one of the craniodigital syndromes, is a rare genetic entity with autosomal recessive inheritance and characterized by pre- and postnatal growth retardation, microcephaly, distinctive facial appearance, developmental delay/intellectual disability, and variable syndactylies of the fingers and toes. In this report, a further female patient of Filippi syndrome who additionally had a unilateral congenital talipes equinovarus (CTEV), a feature not previously recorded, is described. Genetic testing revealed a novel homozygous frameshift pathogenic variant (c.552_555delCAAA, p.Asn184Lysfs*8) in CKAP2L and thus confirmed the diagnosis of Filippi syndrome. We hope that the newly recognized feature (CTEV) will contribute to expand the clinical spectrum of this extremely rare condition. In view of the paucity of reported cases, the full spectrum of clinical findings of Filippi syndrome necessitates obviously further affected individuals/pedigrees delineation in order to elucidate the etiological and phenotypic aspects of this orphan disease appropriately.

Smith-Magenis syndrome: Report of morphological and new functional cardiac findings with review of the literature.

Smith-Magenis syndrome (SMS) is a genetic disorder characterized by multiple congenital anomalies, sleep disturbance, behavioral impairment, and intellectual disability. Its genetic cause has been defined as an alteration in the Retinoic Acid-Induced 1 gene. Cardiac anomalies have been reported since the first description of this condition in patients with 17p11.2 deletion. Variable cardiac defects, including ventricular septal defects, atrial septal defects, tricuspid stenosis, mitral stenosis, tricuspid and mitral regurgitation, aortic stenosis, pulmonary stenosis, mitral valve prolapse, tetralogy of Fallot, and total anomalous pulmonary venous connection, have been anecdotally reported and systematic case series are still lacking. Herein, we define the spectrum of the cardiac phenotype and describe for the first time the cardiac function in a large cohort of pediatric patients with SMS. Revision of the literature and correlations between genotype and cardiac phenotype was performed.

The Transition Zone Protein AHI1 Regulates Neuronal Ciliary Trafficking of MCHR1 and Its Downstream Signaling Pathway.

The Abelson-helper integration site 1 (AHI1) gene encodes for a ciliary transition zone localizing protein that when mutated causes the human ciliopathy, Joubert syndrome. We prepared and examined neuronal cultures derived from male and female embryonic Ahi1+/+ and Ahi1-/- mice (littermates) and found that the distribution of ciliary melanin-concentrating hormone receptor-1 (MchR1) was significantly reduced in Ahi1-/- neurons; however, the total and surface expression of MchR1 on Ahi1-/- neurons was similar to controls (Ahi1+/+). This indicates that a pathway for MchR1 trafficking to the surface plasma membrane is intact, but the process of targeting MchR1 into cilia is impaired in Ahi1-deficient mouse neurons, indicating a role for Ahi1 in localizing MchR1 to the cilium. Mouse Ahi1-/- neurons that fail to accumulate MchR1 in the ciliary membrane have significant decreases in two downstream MchR1 signaling pathways [cAMP and extracellular signal-regulated kinase (Erk)] on MCH stimulation. These results suggest that the ciliary localization of MchR1 is necessary and critical for MchR1 signaling, with Ahi1 participating in regulating MchR1 localization to cilia, and further supporting cilia as critical signaling centers in neurons.SIGNIFICANCE STATEMENT Our work here demonstrates that neuronal primary cilia are powerful and focused signaling centers for the G-protein-coupled receptor (GPCR), melanin-concentrating hormone receptor-1 (MCHR1), with a role for the ciliary transition zone protein, Abelson-helper integration site 1 (AHI1), in mediating ciliary trafficking of MCHR1. Moreover, our manuscript further expands the repertoire of cilia functions on neurons, a cell type that has not received significant attention in the cilia field. Lastly, our work demonstrates the significant influence of ciliary GPCR signaling in the overall signaling of neurons.

Phelan McDermid Syndrome: Multiple Sclerosis as a Rare but Treatable Cause for Regression-A Case Report.

Phelan McDermid syndrome (PMcD) is a neurogenetic disease associated with haploinsufficiency of the SHANK3 gene due to a spectrum of anomalies in the terminal region of the long arm of chromosome 22. SHANK3 is the abbreviation for SH3 domain and ankyrin repeat-containing protein, a gene that encodes for proteins of the postsynaptic density (PSD) of excitatory synapses. This PSD is relevant for the induction and plasticity of spine and synapse formation as a basis for learning processes and long-term potentiation. Individuals with PMcD present with intellectual disability, muscular hypotonia, and severely delayed or absent speech. Further neuropsychiatric manifestations cover symptoms of the autism spectrum, epilepsy, bipolar disorders, schizophrenia, and regression. Regression is one of the most feared syndromes by relatives of PMcD patients. Current scientific evidence indicates that the onset of regression is variable and affects language, motor skills, activities of daily living and cognition. In the case of regression, patients normally undergo further diagnostics to exclude treatable reasons such as complex-focal seizures or psychiatric comorbidities. Here, we report, for the first time, the case of a young female who developed progressive symptoms of regression and a dystonic-spastic hemiparesis that could be traced back to a comorbid multiple sclerosis and that improved after treatment with methylprednisolone.

Genotype and phenotype in 18 Chinese patients with Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS, MIM# 1359200) is a multisystem congenital disorder characterized by coarse facial features, hypoplasia of the fifth digits and nails, and intellectual disability. It is a genetically heterogeneous condition caused by pathogenic variants in genes encoding proteins of the BAF (BRG1-associated factors) chromatin modeling complex and its downstream transcriptional factor. To date over 220 CSS individuals with pathogenic variants found have been described in the literature. This case series reported 18 molecularly confirmed Chinese individuals (17 with ARIDIB (OMIM*614556) variants and one with SMARCB1 (OMIM*601607) variant) from 17 unrelated families in Hong Kong. The clinical features of these 18 Chinese CSS patients together with two previously reported Chinese patients with ARID1B variants were reviewed. Among the 19 Chinese patients with ARID1B variants, our data suggested a lower prevalence of feeding problem, autistic features, agenesis of corpus callosum (ACC) or partial/hypoplasia of corpus callosum, and sparse hair when compared with previous reports. There was appearing higher prevalence of digital hypoplasia. Digital hypoplasia was observed to become less noticeable with time in some patients. This report highlighted the age-dependent phenotypic presentation of CSS and ethnicity-related effect on ARID1B-CSS phenotype. Moreover, this series included the first family with molecularly confirmed maternal somatic mosaicism of ARID1B variant leading to familial CSS recurrence.

Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics.

Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal-recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole-exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto-occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla-spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.

X-linked frontometaphyseal dysplasia with severe scoliosis and spinal cord compromise in an Indian boy.

Frontometaphyseal dysplasia (FMD) is a rare genetic disorder with morphological abnormalities of the skeletal and extra skeletal tissues. It belongs to the group of otopalatodigital spectrum disorders. Here we report a 12-year-old boy from India with features of frontometaphyseal dysplasia who had severe scoliosis with neurological complications due to spinal cord compromise. Clinical examination of his mother also revealed mild features of FMD. The manuscript highlights the clinical presentation of the disorder and discusses the clinical heterogeneity of the otopalatodigital spectrum disorders.

Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.

Common pathogenesis for sirenomelia, OEIS complex, limb-body wall defect, and other malformations of caudal structures.

Decades of clinical, pathological, and epidemiological study and the recent application of advanced microarray and gene sequencing technologies have led to an understanding of the causes and pathogenesis of most recognized patterns of malformation. Still, there remain a number of patterns of malformation whose pathogenesis has not been established. Six such patterns of malformation are sirenomelia, VACTERL association, OEIS complex, limb-body wall defect (LBWD), urorectal septum malformation (URSM) sequence, and MURCS association, all of which predominantly affect caudal structures. On the basis of the overlap of the component malformations, the co-occurrence in individual fetuses, and the findings on fetal examination, a common pathogenesis is proposed for these patterns of malformation. The presence of a single artery in the umbilical cord provides a visible clue to the pathogenesis of all cases of sirenomelia and 30%-50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWD. The single artery is formed by a coalescence of arteries that supply the yolk sac, arises from the descending aorta high in the abdominal cavity, and redirects blood flow from the developing caudal structures of the embryo to the placenta. This phenomenon during embryogenesis is termed vitelline vascular steal.

Clinical characterization of individuals with the distal 1q21.1 microdeletion.

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.