Whole-exome-based single nucleotide variants and copy number analysis for prenatal diagnosis of compound heterozygosity of SMPD4.

BACKGROUND: Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with neurodevelopmental disorders with microcephaly, arthrogryposis, and structural brain anomalies. SMPD4 encodes a sphingomyelinase that hydrolyzes 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. MATERIALS AND METHODS: For the efficient prenatal diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using whole-exome analysis is required. A physical examination of the parents was performed. Karyotype and whole-exome analysis were performed for the fetus and the parents. RESULTS: A fetus with microcephaly and arthrogryposis; biallelic null variants (c.387-1G>A; Chr2[GRCh38]: g.130142742_130202459del) were detected by whole-exome sequencing (WES). We have reported for the first time the biallelic loss-of-function mutations in SMPD4 in patients born to unrelated parents in China. CONCLUSION: WES could replace chromosomal microarray analysis and copy number variation sequencing as a more cost-effective genetic test for detecting CNVs and diagnosing highly heterogeneous conditions.

Prenatal diagnosis (or lack thereof) of arthrogryposis multiplex congenita and its impact on the perinatal experience of parents: A retrospective survey.

OBJECTIVE: To examine parental experiences during pregnancies affected by Arthrogryposis Multiplex Congenita (AMC) by identifying commonalities, risk factors, and areas for improvement in detection rates, care protocols, and patient experience. STUDY DESIGN: An online survey was distributed via AMC support groups on Facebook. Topics included demographics, risk factors, parental recall of sonographic findings, delivery characteristics and neonatal findings. Responses were divided into antenatally detected cases (ADCs) and postnatally detected cases (PDCs). Quantitative responses were analyzed with the Fisher exact test. Qualitative data were analyzed with thematic analysis. RESULTS: The antenatal detection rate of arthrogryposis was 37%. Decreased fetal movement was reported by 53% and early bleeding by 21%. Sonographic findings in ADCs included clubfoot (83%), clenched hand (51%), decreased fetal movement (50%), elbow contracture (51%), and knee contracture (46%). Among ADCs, 29% delivered vaginally and 71% delivered by cesarean versus PDCs (44% vaginal, 56% cesarean). Neonatal intensive care unit admission rate was 63%. Bone fracture occurred in 9%. Detection led to a planned change in delivery mode in 33% and location in 50%. Among ADCs, 17% felt their concerns were not adequately addressed versus 43% of PDCs. CONCLUSIONS: Antenatal detection of arthrogryposis was low. We propose enhanced screening criteria to aid prenatal diagnosis and promote utilization of more robust practice guidelines.

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

Growth Charts for Children With Arthrogryposis Multiplex Congenita.

Children with arthrogryposis multiplex congenita (AMC) often demonstrate growth differences compared with typically developing (TD) children. However, growth charts have not been developed for this population. The purpose of this study was to create AMC-specific growth charts and to compare these values to those of TD children. A retrospective review of height/length and weight for 206 children with AMC was performed. Growth charts were developed and stratified over seven percentiles; these were then compared with growth charts of TD children. Children with AMC tend to be smaller in stature and weight compared with TD children, particularly in the first 36 months of life. Thereafter, weight values trend toward the 50th percentile of TD children, but height/length values persist around the 5th percentile of TD children. The development of AMC-specific growth charts provides health care providers an objective tool to evaluate growth patterns of patients with AMC.

Biallellic variants in CACNA1S cause fetal akinesia sequence, progressive hydrops and stillbirth.

Fetal arthrogryposis is a well-recognised ultrasonographic phenotype, caused by both genetic, maternal and extrinsic factors. When present with fetal growth restriction, pulmonary hypoplasia and multiple joint contractures, it is often referred to as fetal akinesia deformation sequence (FADS). Historically, elucidating genetic causes of arthryogryposis/FADS has been challenging; there are now more than 150 genes known to cause arthrogryposis through myopathic, neuromuscular and metabolic pathways affecting fetal movement. FADS is associated with over 400 medical conditions making prenatal diagnosis challenging. Here we present a case of FADS diagnosed at 19 weeks gestation with progression to severe fetal hydrops and stillbirth at 26-weeks gestation. Initial investigations including combined first trimester screening, TORCH (infection) screen and chromosomal microarray were normal. Trio whole exome sequencing (WES) detected compound heterozygous likely pathogenic CACNA1S gene variants associated with autosomal dominant (AD) and autosomal recessive (AR) congenital myopathy and FADS. To our knowledge, this is the first prenatal diagnosis of this condition.

Muscular phenotype description of abnormal THOC2 splicing.

Until recently, the disease known to be associated with THOC2 mutations was Intellectual developmental disorder, X-linked 12 (MIM300957). However, recently, fetal arthrogryposis multiplex congenita has been associated with a specific splice site mutation in the THOC2 gene. We report a family with the same splice site mutation in the THOC2 gene involved in fetal arthrogryposis as well. We provide the first description of the muscular phenotype of this disease which reveals the presence of cytoplasmic bodies. Our findings expand the clinical phenotype of THOC2 gene related defects.

Identification of two novel MYH3 variants causing different phenotypes in prenatal diagnosis.

The MYH3 gene encodes the embryonic myosin heavy chain, which is crucial for the skeletal and muscular development. The MYH3 variants are associated with distal arthrogryposis type 2A (Freeman-Sheldon syndrome), distal arthrogryposis type 2B3 (Sheldon-Hall syndrome), CPSFS1A (Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A) and CPSFS1B, which have some shared characteristics and great variability of clinical phenotypes. In this study, we report two novel MYH3 missense variants c.1024T>G (p.Phe342Val) and c.3872A>C (p.Gln1291Pro), demonstrating different phenotypes in the prenatal setting. This study expands the spectrum of MYH3 variants and supports the domain-specific genotype-phenotype correlation of MYH3.

Mutation In Fkbp10 Gene Cause Bruck Syndrome 1 (Brks1) In A Pakistani Family Of Pashtun Origin.

BACKGROUND: Bruck syndrome or BRKS1 is an extremely rare condition characterized by the onset of fractures in infancy, joint contractures, short stature, severe limb deformity, and progressive scoliosis. Less than fifty cases of BRKS1 have been reported so far. Here, we report Bruck syndrome 1 in two siblings who belong to a consanguineous Pashtun family living in Karachi. Our first case is a seven years old boy who presented with recurrent fractures, lower limb deformity, and unable to walk. He had markedly reduced bone mineral density (BMD) and a normal bone profile. The other sibling presented at one week of age with arthrogryposis multiplex congenita, post-axial polydactyly of both feet and spontaneous fracture of the right proximal femur. Genetic testing of our cases was performed in which genomic DNA was enriched for targeted regions using the hybridization-based protocol, and DNA sequencing was done using Illumina technology; both cases were found homozygous for pathogenic variant c.344G>A (p.Arg115Gln) in FKBP10 gene leading to the diagnosis of BRKS1. FKBP10 gene mutation has been reported earlier in association with BRKS1, but in our case report, we have reported the first case of BRKS1, particularly in the Pakistani population of Pashtun ethnicity. We have reported post-axial polydactyly of both feet and spina bifida for the first time in association with FKBP10 mutation. In addition, the skeletal survey of patients with BRKS 1 is elaborated in detail in this report.

DST variants are responsible for neurogenic arthrogryposis multiplex congenita enlarging the spectrum of type VI hereditary sensory autonomic neuropathy.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through whole-exome sequencing combined with arrayCGH from DNA of a fetus presenting with early onset AMC, we identified biallelic loss of function variants in Dystonin (DST): a stop gain variant (NM_001144769.5:c.12208G > T:p.(Glu4070Ter)) on the neuronal isoform and a 175 kb microdeletion including exons 25-96 of this isoform on the other allele [NC_000006.11:g.(56212278_56323554)_(56499398_56507586)del]. Transmission electron microscopy of the sciatic nerve revealed abnormal morphology of the peripheral nerve with severe hypomyelination associated with dramatic reduction of fiber density which highlights the critical role of DST in peripheral nerve axonogenesis during development in human. Variants in the neuronal isoforms of DST cause hereditary sensory and autonomic neuropathy which has been reported in several unrelated families with highly variable age of onset from fetal to adult onset. Our data enlarge the disease mechanisms of neurogenic AMC.

Measurement Repeatability and Reproducibility of Virtual Goniometry of a Set of Acquired Images in Youths with Arthrogryposis Multiplex Congenita.

OBJECTIVES: To evaluate the intra-rater repeatability and the inter-rater reproducibility of using a virtual goniometer to measure upper and lower extremity joint range of motion (ROM) in youths with arthrogryposis multiplex congenita (AMC). METHODS: Youths presenting with AMC aged 8 to 21 years old were recruited. ROM of the upper and lower limbs were assessed remotely during a teleassessment on a video-conferencing platform. Screen captures were taken and ROM were measured by two raters, two-weeks apart, using a virtual goniometer. Intraclass correlation coefficient (ICC) and associated 95% confidence interval (CI) were calculated to assess intra-and inter-rater repeatability and reproducibility. RESULTS: Nine participants were included with a median age of 15.9 years (range: 11.3 to 20.8 years). The overall intra-rater ICC was 0.997 (95% CI:0.996 to 0.997) for the first rater and 0.993 (95% CI:0.992 to 0.994) for the second rater. The inter-rater ICC ranged from 0.410 (95% CI:-0.392; 0.753) for forearm pronation to 0.998 (95% CI:0.996; 0.999) for elbow flexion. CONCLUSIONS: Results of the current study suggest that virtual goniometry is reproducible and repeatable for the ROM of most joints. Future studies should evaluate procedural reliability and validity of the proposed method for youth with complex conditions.

Monomelic Multifocal Neuropathy: An Unrecognized Electrophysiological Feature of Hereditary Neuropathy with Liability to Pressure Palsies in Childhood.

Hereditary neuropathy with liability to pressure palsies (HNPP) is well defined in adults, but its clinical and electrophysiological features in childhood have not been well characterized. We describe a case of HNPP in a child with the unique electrophysiological presentation, affecting only one upper extremity.

Arthrogryposis, renal dysfunction, cholestasis syndrome in a neonate: an uncommon association of common problems.

A male infant born out of non-consanguineous marriage to a primigravida presented to us as his third hospitalisation with ichthyotic lesions all over the body, cholestatic jaundice, multiple joint contractures and a history of recurrent sepsis. Blood and urine investigations revealed Fanconi syndrome, hypothyroidism and direct hyperbilirubinaemia with elevated liver enzymes and normal gamma glutamyl transpeptidase levels. The combination of arthrogryposis, renal dysfunction and cholestasis led to the suspicion of arthrogryposis, renal tubular dysfunction, cholestasis (ARC) syndrome, which was then proved by genetic testing. The baby was managed conservatively with respiratory support, antibiotics, multivitamins, levothyroxine and other supportive measures but succumbed to the illness on day 15 of hospitalisation. Genetic analysis using next-generation sequencing was confirmatory of a homozygous mutation in VIPAS39 gene leading to ARC syndrome type 2 in the present case. Genetic counselling was provided and prenatal testing was advised to the parents for future pregnancies.

The range of publications on arthrogryposis multiplex congenita from 1995 to 2022-A scoping review.

Arthrogryposis multiplex congenita (AMC) is defined as "a group of congenital conditions characterized by joint contractures in two or more body areas." Given its heterogeneity, the definition of AMC has changed multiple times. This scoping review provides an overview of how AMC is defined in scientific publications, on existing knowledge and trends regarding the concept of AMC. Our review illuminates possible knowledge gaps and provides directions for future research. A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Quantitative studies on AMC from 1995 to date were included. We summarized information about definitions/descriptions of AMC, study objectives, study designs, methods, funding, and involvement of patient organizations. A total of 2729 references were screened, and 141 articles fulfilled our inclusion criteria. Our scoping revealed that the majority of publications were cross-sectional or retrospective studies of children and young people, commonly about orthopedic management. Explicit or good definitions of AMC were provided in 86% of the cases. Recent publications on AMC mostly used consensus-based definitions. The research gaps were primarily related to adults, aging, etiology, and new medical treatment, in addition to implications on daily life.

Mental health in adults living with arthrogryposis multiplex congenita.

Little is known about the mental well-being of adults living with arthrogryposis multiplex congenita (AMC). The objectives of this study were to determine the incidence of depression in an international population of adults with AMC and to identify variables independently associated with depression. This cross-sectional study used independent samples t-test and hierarchical multiple regression. The mean Hospital Anxiety and Depression Scale-depression (HADS-D) score of our sample, which included 60 adults with AMC, was 4.0 ± 3.6, with 19% having some signs of depression. Occupation status, age, sex, physical independence, environmental factors, anxiety, and fatigue explained 52.2% of the variance in HADS-D. The prevalence of depression in an adult sample of individuals with AMC is similar to that of the general adult population in the United States. Beyond direct interventions to ameliorate depression, rehabilitation clinicians may also consider treatments and interventions to decrease anxiety and reduce fatigue and environmental barriers.

Similar Cognitive Skill Impairment in Children with Upper Limb Motor Disorders Due to Arthrogryposis Multiplex Congenita and Obstetrical Brachial Plexus Palsy.

Arthrogryposis multiplex congenita (AMC) and obstetrical brachial plexus palsy (OBPP) are motor disorders with similar symptoms (contractures and the disturbance of upper limb function). Both conditions present as flaccid paresis but differ from each other in the pathogenesis: AMC is a congenital condition, while OBPP results from trauma during childbirth. Despite this difference, these diseases are identical in terms of their manifestations and treatment programmes. We compared the cognitive skills of children with AMC and OBPP diagnoses with those of healthy children; we also compared the motor skills of impaired children with those of healthy ones. The patients in both groups significantly differed from the healthy children with regard to psychological parameters, such as 'visual memory capacity' and 'thinking'. Moreover, the two groups with children with AMC and OBPP significantly differed from each other in motor skill parameters, such as 'delayed motor development', 'general motor development', and the 'level of paresis'. Upper limb motor function in the OBPP children was less impaired compared to that of the AMC children. However, we did not find any significant differences in cognitive deficits between the AMC children and the OBPP children. This may indicate that motor impairment is more significant than the underlying cause for the development of cognitive impairment; however, the factors causing this phenomenon require further study (e.g., social environment, treatment, and rehabilitation programme).

Novel Arthrogryposis Multiplex Congenita Presentation in a Newborn With Pierpont Syndrome.

Pierpont syndrome is a rare and recently described multiple congenital anomaly syndrome, classically characterized by global developmental delay, distinctive facial dysmorphic features, and abnormal fat distribution in distal limbs. Only few cases were previously documented. We report a case of a term male neonate admitted to the neonatal intensive care unit because of feeding difficulties. Intrauterine growth restriction, microcephaly, and bilateral equinovarus foot were diagnosed in the second trimester, and prenatal array comparative genomic hybridization showed no abnormality. Physical examination revealed bilateral flexion deformities of wrists, elbows, knees and clubfoot, large hands and feet, deep palmar and plantar grooves, and calcaneo-plantar fat pads. Craniofacial dysmorphism, axial hypotonia, and hypoactivity were also observed. Due to the presence of congenital and non-progressive joint contractures, arthrogryposis multiplex congenita (AMC) was considered. A comprehensive diagnostic workup, including a Next Generation Sequencing target panel, was performed but did not establish a diagnosis. The clinical exome identified an heterozygous pathogenic variant in the TBL1XR1 gene (NM_001321194.1: c.1337A>G, p.[Tyr446Cys]), allowing Pierpont syndrome diagnosis. Our case stands out for reporting the novel AMC presentation in a Pierpont syndrome newborn. The broader and precocious genetic testing proved to be an essential clarifying diagnostic tool. Our patient supports the relation between the p.Tyr446Cys sequence variant in TBL1XR1 gene with this rare syndrome, reinforcing its association with a distinctive and recognizable phenotype, as well as expanding its clinical features to include AMC.

Expanding the phenotype of Bruck syndrome: Severe limb deformity, arthrogryposis, congenital cardiac disease and pulmonary hemorrhage.

Bruck syndrome is a rare collagen disorder with autosomal recessive inheritance caused by pathogenic variants in either FKBP10 or PLOD2 genes. It is characterized by bone fragility and fractures similar in severity and variability to osteogenesis-imperfecta as well as congenital joint contractures. This article describes an infant with a homozygous (partial) gene deletion of PLOD2 that includes the start codon and would be expected to lead to nonfunctional protein product. The infant had a severe phenotype of Bruck syndrome and is the only reported case of Bruck syndrome with congenital cardiac disease (triscuspid valve dysplasia with severe regurgitation, mitral valve prolapses with moderate regurgitation, and pulmonary hypertension) and pulmonary hemorrhage. We hypothesize that the additional feature of congenital cardiac disease in this case was due to the underlying defect in type I collagen, and that the pulmonary hemorrhage was multifactorial, with underlying vessel fragility, rib fractures, and high pulmonary pressures likely to be major contributing factors. Management was largely supportive with the use of bisphosphonates to assist in pain management. Care was complicated by comorbid cardiopulmonary compromise, limited evidence-base guiding care, and difficulties in discussing end-of-life care.

Lethal respiratory course and additional features expand the phenotypic spectrum of PIEZO2-related distal arthrogryposis type 5.

Distal arthrogryposes (DA) are a group of conditions presenting with multiple congenital contractures in the distal joints. The 10 types of DA are distinguished by different extra-articular manifestations. Heterozygous gain-of-function variants in PIEZO2 are known to cause a spectrum of DA conditions including DA type 3, DA type 5, and possibly Marden Walker syndrome, which are usually distinguished by the presence of cleft palate (DA3), ptosis and restriction in eye movements (DA5), and specific facial abnormalities and central nervous system involvement, respectively. We report on a boy with a recurrent de novo heterozygous PIEZO2 variant in exon 20 (NM_022068.3: c.2994G > A, p.(Met998Ile); NM_001378183.1: c.3069G > A, p.(Met1023Ile)), who presented at birth with DA and later developed respiratory insufficiency. His phenotype broadly fits the PIEZO2 phenotypic spectrum and potentially extends it with novel phenotypic features of pretibial linear vertical crease, immobile skin, immobile tongue, and lipid myopathy.

Ichthyosis, petechiae, and arthrogryposis in a neonate.

Gaucher disease is a rare lysosomal storage disorder caused by a deficiency in glucocerebrosidase. This enzyme deficiency leads to the accumulation of toxic metabolites in various organs. Multiple subtypes of this disease have been described; however, the perinatal-lethal form is extremely rare and challenging to diagnose. We present a case of a newborn girl with ichthyosis, petechiae, and arthrogryposis, later found to be homozygous for a pathogenic variant of the glucocerebrosidase gene. This case highlights the potential role of dermatologists in the recognition of this rare disease.

Fetal akinesia deformation sequence syndrome associated with recessive TTN variants.

Arthrogryposis multiplex congenita (AMC) [also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS)] is etiologically a heterogeneous condition with an estimated incidence of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single-gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720-731). The introduction of next-generation gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants. Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/compound heterozygous pathogenic variants in the TTN.