PurposeHaploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS.MethodsWe report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status.ResultsThe expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes.ConclusionWe refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.

Background Musculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS- CHST14 ) or DSE (mcEDS- DSE ). Although 48 patients in 33 families with mcEDS- CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. Methods We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS- CHST14 through international collaborations. Results Sixty-six patients in 48 families (33 males/females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS- CHST14 than in eight reported patients with mcEDS- DSE . Conclusion This first international collaborative study of mcEDS- CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

Background Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described. Methods Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation. Results Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1). Conclusions Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

Background We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Chondrodysplasia punctata (CDP) is an etiologically heterogeneous disorder characterized by the radiographic finding of stippled epiphyses (punctate calcifications). It is often accompanied by a characteristic facial appearance, known as the Binder phenotype, which is attributed to hypoplasia of the nasal cartilages; abnormal distal phalanges (brachytelephalangy) are a common component manifestation as well. We report eight patients with a Binder phenotype with or without CDP who all shared a known or suspected maternal deficiency of vitamin K. We suspect that this phenotype is probably under recognized, and we hope to increase awareness about the maternal risk factors, especially hyperemesis gravidarum, which lead to nutritional deficiency. © 2013 Wiley Periodicals, Inc.

A patient with syndromic Duane retraction syndrome harbors a chromosome 811.1q13.2 inversion and 8p11.1-q12.3 marker chromosome containing subregions with differing mosaicism and allele frequencies. This case highlights the potential requirement for multiple genetic methods to gain insight into genotype-phenotype correlation, and ultimately into molecular mechanisms that underlie human disease.

Infantile hypertrophic pyloric stenosis (IHPS), the most common surgical condition producing emesis in infancy, was first described by Hirschsprung [1] in 1888. Ramstedt performed the first successful pyloromyotomy in 1912; however, most cases were lethal at that time. Although advances in medical knowledge and care have resulted in minimal mortality and morbidity today, the cause of IHPS remains unclear [2]. This article provides an update on IHPS, focusing on pathogenesis, diagnosis and treatment, descriptive epidemiology and associated risk factors, and current understanding of the role of genetics.

Objective: The 4q– syndrome comprises all microscopically visible deletions of the long arm of chromosome 4. Cases with 4q deletions represent a diverse group that share several phenotypic characteristics. We report the prenatal diagnosis of an isolated terminal 4q33 deletion in a fetus with hydrops. Method: A comprehensive workup, including an amniocentesis, was performed on a 32-week fetus presenting with massive hydrops and polyhydramnios. Results: The karyotype obtained from the amniotic fluid showed an unusual banding pattern on chromosome 4q. Fluorescent in situ hybridization revealed a 4q33-qter deletion. The proband shared several of the phenotypic characteristics of the 4q– syndrome. Multidisciplinary evaluation of the newborn confirmed the genotype and failed to identify another cause for the hydrops. Conclusion: We suggest that the broad spectrum of phenotypes expressed by patients with terminal 4q33 deletions includes hydrops fetalis.

Autosomal recessive cutis laxa is a genetically heterogeneous condition. Its molecular basis is largely unknown. Recently, a combined disorder of N- and O-linked glycosylation was described in children with congenital cutis laxa in association with severe central nervous system involvement, brain migration defects, seizures and hearing loss. We report on seven additional patients with similar clinical features in combination with congenital disorder of glycosylation type IIx. On the basis of phenotype in 10 patients, we define an autosomal recessive cutis laxa syndrome. The patients have a complex phenotype of neonatal cutis laxa, transient feeding intolerance, late closure of the fontanel, characteristic facial features including down-slanting palpebral fissures, short nose and small mouth, and developmental delay. There is a variable degree of the central nervous system involvement and variable systemic presentation. The biochemical analysis using transferrin isoelectric focusing gives false negative results in some of the youngest patients. Analysis of the apolipoprotein C-III isoelectric focusing, however, is diagnostic in all cases.