SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes.

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyses sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes (NPC). We refine the clinical phenotype of loss-of-function SMPD4 variants by describing five individuals from three unrelated families with longitudinal data due to prolonged survival. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. We studied the function of SMPD4 at the cellular and organ levels. Knock-down of SMPD4 in human neural stem cells causes reduced proliferation rates and prolonged mitosis. Moreover, SMPD4 depletion results in abnormal nuclear envelope breakdown and reassembly during mitosis and decreased post-mitotic NPC insertion. Fibroblasts from affected individuals show deficient SMPD4-specific neutral sphingomyelinase activity, without changing (sub)cellular lipidome fractions, which suggests a local function of SMPD4 on the nuclear envelope. In embryonic mouse brain, knockdown of Smpd4 impairs cortical progenitor proliferation and induces premature differentiation by altering the balance between neurogenic and proliferative progenitor cell divisions. We hypothesize that, in individuals with SMPD4-related disease, nuclear envelope bending, which is needed to insert NPCs in the nuclear envelope, is impaired in the absence of SMPD4 and interferes with cerebral corticogenesis and survival of pancreatic beta cells.

Management of an older Marshall-Smith syndrome patient: a review of literature of MSS and craniosynostosis.

Marshall-Smith Syndrome (MSS) is a rare progressive developmental disorder that severely impairs a patient's intellectual development and physical health. The only known cause for MSS is a mutation in the nuclear factor 1 X (NFIX) gene. This mutation affects neuronal development and protein transcription. Historically, most patients with MSS do not survive beyond 3 years of age. Reports of ocular findings are limited. We report a case of a 9-year-old MSS patient with progressive craniosynostosis, elevated intracranial pressure, and catastrophic ocular complications. A comprehensive PubMed literature search from 2018 to August 2022 updating a previous review of older literature produced 72 articles relating to MSS, which are reviewed.

Long-term outcomes in ALG13-Congenital Disorder of Glycosylation.

ALG13-CDG is a rare X-linked disorder of N-linked glycosylation. Given the lack of long-term outcome data in ALG13-CDG, we collected natural history data and reviewed individuals surviving to young adulthood with confirmed pathogenic variants in ALG13 in our own cohort and in the literature. From the 14 ALG13-CDG patients enrolled into our Frontiers of Congenital Disorders of Glycosylation Consortium natural history study only two patients were older than 16 years; one of these two females is so far unreported. From the 52 patients described in the medical literature with confirmed pathogenic variants in ALG13 only five patients were older than 16 years (all females), in addition to the new, unreported patient from our natural history study. Two male patients have died due to ALG13-CDG, and there were no surviving males older than 16 years with a confirmed ALG13-CDG diagnosis. Our adolescent and young adult cohort of six patients presented with epilepsy, muscular hypotonia, speech, and developmental delay. Intellectual disability was present in all female patients with ALG13-CDG. Unreported features included ataxia, neuropathy, and severe gastrointestinal symptoms requiring G/J tube placement. In addition, two patients from our natural history study developed unilateral hearing loss. Skeletal abnormalities were found in four patients, including osteopenia and scoliosis. Major health problems included persistent seizures in three patients. Ketogenic diet was efficient for seizures in three out of four patients. Although all patients were mobile, they all had severe communication problems with mostly absent speech and were unable to function without parental support. In summary, long-term outcome in ALG13-CDG includes gastrointestinal and skeletal involvement in addition to a chronic, mostly non-progressive neurologic phenotype.

MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects.

Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

46,XY DSD and limb abnormalities in a female with a de novo LHX9 missense mutation.

Differences in sex development (DSD) are a group of rare conditions involving genes, hormones and reproductive organs, including genitals. Although these disorders are common, information about the molecular causes remain limited. Many genes have been identified in association with DSD but in many cases the causative gene could not be identified. The Lhx9 gene has been studied in mice and birds, and biallelic mutations in this gene have been found to cause 46,XY DSD and limb abnormalities. So far two variants of LHX9 have been identified in 46,XY individuals with testicular regression, micropenis and hypospadias. We report a de novo heterozygous missense variant in LHX9 in a girl with 46,XY DSD and finger and toe abnormalities. It was previously predicted that a mutation in LHX9 would not cause extragenital anomalies in light of prior animal studies, but our report adds to the limited knowledge of the phenotype observed in humans with a variant in LHX9. To the best of our knowledge this is the first reported case with this combination of abnormalities.

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

Beyond circles and squares: A commentary on updating pedigree nomenclature to better represent patient diversity.

With changes in our understanding of gender identity and disorders of sex differentiation (DSDs), as well as a need to promote medical care that appropriately reflects the intersectional personal identities of patients with respect to sex and gender, we explored possible modifications of pedigree nomenclature to better represent such patient diversity. There are currently no widely accepted standard symbols to simultaneously represent both gender identity and assigned sex at birth within a pedigree. Previous studies assessing perspectives from members of the transgender and gender non-binary (TGNB) community have highlighted the need for a unique symbol to represent non-binary individuals and better ways to represent core gender identities for gender minorities such as transgender individuals. In our experience we have encountered similar dilemmas with documentation for individuals with DSDs in terms of a lack of unequivocal symbolic representation within the pedigree. Here we propose three distinct symbols for gender identity combined with superscript symbols to represent sex assigned at birth, which we think may unequivocally represent TGNB individuals and patients with DSDs. It is clear that further research is needed to ensure that any proposed changes are acceptable by and respectful of all patients regardless of their gender identity and assigned sex at birth. We hope that further research will include focus groups and surveys to get broader input from gender minority stakeholders so that new standards can be developed and modified as we strive to meet the needs of our increasingly diverse patient population.

Wolf-Hirschhorn Syndrome with Hyperparathyroidism: A Case Report and a Narrative Review of the Literature.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.

Tetrasomy 15q26: a distinct syndrome or Shprintzen-Goldberg syndrome phenocopy?

PURPOSE: The aim of this study was to characterize the clinical phenotype of patients with tetrasomy of the distal 15q chromosome in the form of a neocentric marker chromosome and to evaluate whether the phenotype represents a new clinical syndrome or is a phenocopy of Shprintzen-Goldberg syndrome. METHODS: We carried out comprehensive clinical evaluation of four patients who were identified with a supernumerary marker chromosome. The marker chromosome was characterized by G-banding, fluorescence in situ hybridization, single nucleotide polymorphism oligonucleotide microarray analysis, and immunofluorescence with antibodies to centromere protein C. RESULTS: The marker chromosomes were categorized as being neocentric with all showing tetrasomy for regions distal to 15q25 and the common region of overlap being 15q26→qter. CONCLUSION: Tetrasomy of 15q26 likely results in a distinct syndrome as the patients with tetrasomy 15q26 share a strikingly more consistent phenotype than do the patients with Shprintzen-Goldberg syndrome, who show remarkable clinical variation.

Pulmonary complications of genetic disorders.

Many different pulmonary manifestations are seen in conjunction with genetic disorders. Pulmonary findings have been noted with some cytogenetic conditions, many single gene or mendelian disorders, as well as with a number of inborn errors of metabolism. In addition, congenital lung anomalies are relatively common, occurring as isolated anomalies and as part of multiple anomaly syndromes. Recognition of pulmonary problems in patients with genetic disorders may lead to prompt treatment and intervention, which ultimately might translate into improved outcome. This review is focused on the clinical aspects rather than the basic science; comprehensive reviews on specific disease entities are readily available.

A Case of Growth Hormone Use in Dyggve-Melchior-Clausen Syndrome.

Short stature has many causes including genetic disease, skeletal dysplasias, endocrinopathies, familial short stature, and nutritional deficiencies. Recombinant growth hormone (rGH) therapy may be employed to improve stature based on the underlying etiology and growth velocity. Skeletal dysplasia in Dyggve-Melchior-Clausen (DMC) syndrome tends to be progressive, typically with hip involvement, and ultimately leads to bilateral dislocation of the hip joints. Here, we present a pediatric patient with short stature treated with rGH therapy, complicated by the development of debilitating, bilateral hip pain, and found to have DMC syndrome. Our patient had limited range of motion at several joints including the hips after receiving 6 months of rGH therapy. Given the timing of the patient's rGH therapy and the progression of her disease, it is difficult to determine if there were any benefits and instead, is concerning for worsening of her skeletal dysplasia with rGH therapy use. Consequently, patients with severe short stature should have a thorough workup for genetic causes like DMC syndrome, before initiating rGH therapy to determine any potential benefits or harms of treatment.

A trauma-informed approach to the pediatric COVID-19 response.

To effectively care for children during COVID-19, pediatricians need to appreciate the stress and potential traumatic effect of the pandemic. By employing the "CARES" framework, pediatric providers can openly discuss the pandemic with patients and families, collaborate to build resiliency, and encourage engagement in activities and resources that are protective. This approach could potentially prevent both the short and long term health consequences resulting from the toxic stress and traumatic exposure of COVID-19. Pediatricians are uniquely positioned to mitigate the extent to which the pandemic affects the nation's children and we believe it is our responsibility to do so, to uphold the health and wellness of pediatric patients across their lifespan.

Pulmonary Manifestations of Genetic Disorders in Children.

Congenital bronchopulmonary malformations are relatively common and arise during various periods of morphogenesis. Although some are isolated or sporadic occurrences, others may result from single gene mutations or cytogenetic imbalances. Single gene mutations have been identified, which are etiologically related to primary pulmonary hypoplasia, lung segmentation defects as well as pulmonary vascular and lymphatic lesions. Functional defects in cystic fibrosis, primary ciliary dyskinesias, alpha-1-antitrypsin deficiency, and surfactant proteins caused by gene mutations may result in progressive pulmonary disease. This article provides an overview of pediatric pulmonary disease from a genetic perspective.

Natural Progression and Symptomatic Management of Tarsal-Carpal Coalition Syndrome: A Case Report.

CASE: Tarsal-carpal coalition syndrome (TCCS) is a disorder identified by fusion of the carpals, tarsals, and phalanges of the hands and feet. We describe a case of an 11-year-old girl who has been followed at our outpatient clinic from the age of 8 months. CONCLUSION: Although patients with TCCS can experience a wide range of symptoms, the primary complaint arises from the foot deformity and associated pain. Using advanced imaging such as 3D computed tomography reconstruction and genetic testing, this report details the clinical, genetic, and radiographic characteristics of the disorder. We highlight the natural progression and symptomatic management of TCCS.

Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms.

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

Primary care pediatricians' satisfaction with subspecialty care, perceived supply, and barriers to care.

OBJECTIVES: To compare satisfaction with specialty care by primary care pediatricians (PCPs), perceived barriers to care, and adequacy of specialist supply. STUDY DESIGN: A survey of U.S. pediatricians was conducted in 2007. PCPs were asked about satisfaction with specialty care for their patients, as well as supply of specific pediatric subspecialists. Responses of rural and nonrural PCPs were compared regarding 10 potential barriers to care. RESULTS: Most PCPs are satisfied with the quality of subspecialty care. However, they were not satisfied with wait times for appointments, and the availability of many pediatric medical subspecialties and several pediatric surgical specialties. Rural PCPs were significantly more likely to report these shortages compared with nonrural pediatricians; these included 9 of the 18 medical and 5 of the 7 surgical specialties. In addition to wait times for appointments, PCPs reported that subspecialists' nonparticipation in health insurance plans and lack of acceptance of uninsured patients were also barriers to obtaining subspecialty care for their patients. CONCLUSIONS: PCPs provide valuable insight into access to the pediatric subspecialty workforce. This survey of PCPs raises significant concerns about the adequacy of children's access to pediatric subspecialists, especially in rural communities.

Adverse Childhood Experiences: A Case-Based Workshop Introducing Medical Students to Trauma-Informed Care.

Introduction: A large body of evidence implicates adverse childhood experiences (ACEs) as significant factors in shaping adult health outcomes. Despite their wide-ranging impact on health, training on ACEs is lacking in most medical school curricula. As part of a required health equity course for first-year medical students, we developed a novel workshop on ACEs with an introduction to protective effects of resilience and trauma-informed care. Methods: This educational module on ACEs incorporated a didactic session on the science and health consequences of ACEs and best practices for trauma-informed care, followed by a facilitated case discussion in small groups exploring an ACE survey tool and a resilience questionnaire. Results: A total of 535 first-year medical students participated in the workshop in academic years 2016-2017, 2017-2018, and 2018-2019. In the session evaluation, students reported that the small-group, case-based discussion provided the richest learning experience. Areas identified by the students for improvement included delving more deeply into how to incorporate asking about ACEs in clinical care and how to involve multidisciplinary services in addressing ACEs. Discussion: The focus on raising awareness of the health impact of ACEs as well as enhancing resilience using a case-based approach was successful in meeting the stated objectives for the workshop. Future work will consist of building on this introductory content by designing curricular elements that explore multidisciplinary approaches to ACEs and trauma-informed care interventions in the clinical clerkships.

Carrier screening in individuals of Ashkenazi Jewish descent.

DISCLAIMER: This guideline is designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from this guideline.