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A letter to the editor is presented regarding the ankylosis progressive homolog (ANKH) deletion mutations in patients with craniometaphyseal dysplasia.

Introduction: Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation METHODS: We report extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported., Results: Our analysis led to splitting the cohort into two entities., Discussion: One group had variants in the cholesterol binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of TRKB activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity and hyperphagia., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Haploinsufficiency 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., Methods: We 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., Results: The 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., Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature., Competing Interests: Conflict of Interest The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics. The other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)

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., Competing Interests: Competing interests: KM, AT and RP are employed by GeneDx, and XW, WB, JAR receive salary support from Baylor Genetics Laboratory. Both laboratories offer extensive genetic laboratory testing, including exome sequencing and derive revenue from this activity., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: SFT is a consultant of Janssen Pharmaceuticals, Inc., Pfizer Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and co-founder of NeurOp Inc., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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., (Copyright © 2013 Wiley Periodicals, Inc.)

A case is presented of a female newborn infant delivered with an Apgar Score of 1, who could not be resuscitated. There was a high arched palate, bell-shaped chest, contractures of writes inflexion, ankles and knees in extension, and intrauterine fractures. Clinical discussion led to a diagnosis of arthrogryposis secondary to fetal akinesia syndrome caused by nemaline myopathy. Pathology and pathologic discussion confirmed this diagnosis.

We report on a 3.5-year-old girl with a mosaic karyotype including full trisomy 18, normal cells and a majority of cells with partial trisomy involving an extra chromosome 18 deleted at band q22. She had cardiac and CNS anomalies, dysmorphic facial features failure to thrive and developmental delay. A gastrostomy tube was placed at 2 years of age. The combination of improved nutrition and optimal developmental therapy has led to her sitting supported, attempting to stand and enhancement of her cognitive and non-verbal communication abilities. Molecular investigation of the patient and her parents using microsatellite analysis has led to the conclusion that, as expected, the additional copy of chromosome 18 constituting the full trisomic cell line is maternal meiosis I in origin. The data, however, indicate that in the trisomic cell line containing the deleted chromosome 18q, the structurally abnormal 18 was of paternal origin. We think this case is the first described with both structural and numerical trisomic mosaicism involving chromosome 18 in a liveborn infant. We propose a mechanism of origin and review the literature, comparing the clinical presentation of this case with individuals having full or partial trisomy 18., (Copyright 2001 Wiley-Liss, Inc.)

The Aarskog (facial-digital-genital) syndrome is an X-linked disorder in which short stature is accompanied by hypertelorism, digital anomalies, and shawl scrotum. Except for hypertelorism and blepharoptosis, ophthalmic abnormalities have been rarely noted in this condition. We examined four patients who had Aarskog syndrome and unilaterally or bilaterally decreased vision on initial examination. Three family members had V-pattern esotropia, latent nystagmus, inferior oblique overaction, and amblyopia. A fourth patient had bilateral blepharoptosis and severe astigmatism. Other ocular features included hyperopia, anisometropia, deficient ocular elevation, blue sclerae, and posterior embryotoxon. These findings underscore the need for ophthalmic examination in asymptomatic patients with Aarskog syndrome to rule out treatable causes of visual loss.

Fragile X syndrome is the second most common chromosomal cause of mental retardation (MR). The calculated incidence is 1/1000, making accurate and early diagnosis important for specific preventive, pharmacologic, and cognitive treatment. The timely diagnosis in males is facilitated by the characteristic phenotype and an association with autism. In contrast, in females heterozygous for fragile X, the characteristic phenotype and infantile autism are rarely reported. We present two females with cytogenetic expression of the fragile X chromosome for whom the studies were performed because of the presence of autism or prominent autistic features and a behavioral and physical phenotype consistent with fragile X syndrome. The first female, age three years, has autism, hyperactivity, echolalia, language delay, hand stereotypies, and mild MR. The characteristic phenotype was not present nor was there a family history of X-linked MR. Fragile X expression was 6% in the proband, 3% in the mother and 1% (normal) in the father. The second child, seven years old, has prominent autistic features, hyperactivity, mild MR, mild language disorder, and a family history consistent with X-linked MR. Fragile X expression was 3% in the proband and 0% in the mother. These cases support the occurrence of fragile X in autistic females and emphasize the importance of cytogenetic screening for fragile X in this high risk population. Early diagnosis of fragile X allows precise genetic counseling and more specific cognitive and pharmacologic treatment.