Epilepsy is an important feature of KBG syndrome associated with poorer developmental outcome.

OBJECTIVE: The aim of this study was to describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype-phenotype correlation. METHODS: We collected data on patients with ANKRD11 variants by contacting University Medical Centers in the Netherlands, an international network of collaborating clinicians, and study groups who previously published about KBG syndrome. All patients with a likely pathogenic or pathogenic ANKRD11 variant were included in our patient cohort and categorized into an "epilepsy group" or "non-epilepsy group". Additionally, we included previously reported patients with (likely) pathogenic ANKRD11 variants and epilepsy from the literature. RESULTS: We included 75 patients with KBG syndrome of whom 26 had epilepsy. Those with epilepsy more often had moderate to severe intellectual disability (42.3% vs 9.1%, RR 4.6 [95% CI 1.7-13.1]). Seizure onset in patients with KBG syndrome occurred at a median age of 4 years (range 12 months - 20 years), and the majority had generalized onset seizures (57.7%) with tonic-clonic seizures being most common (23.1%). The epilepsy type was mostly classified as generalized (42.9%) or combined generalized and focal (42.9%), not fulfilling the criteria of an electroclinical syndrome diagnosis. Half of the epilepsy patients (50.0%) were seizure free on anti-seizure medication (ASM) for at least 1 year at the time of last assessment, but 26.9% of patients had drug-resistant epilepsy (failure of ≥2 ASM). No genotype-phenotype correlation could be identified for the presence of epilepsy or epilepsy characteristics. SIGNIFICANCE: Epilepsy in KBG syndrome most often presents as a generalized or combined focal and generalized type. No distinctive epilepsy syndrome could be identified. Patients with KBG syndrome and epilepsy had a significantly poorer neurodevelopmental outcome compared with those without epilepsy. Clinicians should consider KBG syndrome as a causal etiology of epilepsy and be aware of the poorer neurodevelopmental outcome in individuals with epilepsy.

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein.

PURPOSE: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. METHODS: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. RESULTS: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. CONCLUSION: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.

ANKRD11 variants: KBG syndrome and beyond.

Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re-evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so-called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.

Prenatal caffeine exposure caused H-type blood vessel-related long bone dysplasia via miR375/CTGF signaling.

Caffeine has developmental toxicity. Prenatal caffeine exposure (PCE) caused intrauterine growth retardation (IUGR) and multiple organ dysplasia. This study intended to explore the effect and mechanism of PCE on long bone development in female fetal rats. In vivo, the PCE group pregnant rats were given different concentrations of caffeine during the gestational Day 9-20. The mRNA expression of osteogenesis-related genes were significantly reduced in PCE group. In the PCE group (120 mg/kg·d), the length and primary center of fetal femur were shorter, and accompanied by H-type blood vessel abundance reducing. Meanwhile, connective tissue growth factor (CTGF) expression decreased in the growth plate of the PCE group (120 mg/kg·d). In contrast, the miR375 expression increased. In vitro, caffeine decreased CTGF and increased miR375 expression in fetal growth plate chondrocytes. After co-culture with caffeine-treated chondrocytes, the tube formation ability for the H-type endothelial cells was decreased. Furthermore, CTGF overexpression or miR375 inhibitor reversed caffeine-induced reduction of tube formation ability, and miR375 inhibitor reversed caffeine-induced CTGF expression inhibition. In summary, PCE decreased the expression of CTGF by miR375, ultimately resulting in H-type blood vessel-related long bone dysplasia.

Temporal bone dysplasia in Coffin-Siris syndrome.

We report a child, diagnosed with Coffin-Siris syndrome (CSS), with chronic right otorrhoea. CT and DR-MRI were performed to further investigate, diagnose and determine relevant surgical anatomy. CT temporal bones assessment was performed, and the measurements compared with previously published data for normal temporal bone anatomy. These comparisons highlighted various differences which were not initially expected; it showed that there were multiple inner ear abnormalities in addition to middle ear disease. This case highlights the importance of considering temporal bone abnormalities in all children with CSS or any dysmorphia, when they may require mastoid procedures. Reviewing the management of this case provides relevant learning opportunities for both primary, secondary and tertiary care institutions.

Musculoskeletal deformities after thoracic surgery in children: An observational long-term follow-up study.

PURPOSE: This study reports the incidence, severity, and predictors of musculoskeletal deformities (MD), including scoliosis and chest wall anomalies, following thoracic procedures in children. METHODS: Children younger than 14 years who had thoracic surgery between 1997 and 2012 and had no other predispositions to MD, underwent longitudinal follow-ups with dedicated musculoskeletal examination performed in an esophageal atresia, orthopedic, or research clinic. Incidence of MD was calculated, and logistic regression methods were used to determine independent predictors, including sex, gestational age, age at procedure, serratus anterior muscle division, and chest tube placement. RESULTS: The study cohort consisted of 104 patients followed for a median of 10.8 years (range 3-21). A total of 56 MD developed in 41 patients (39%), including scapular winging (24; 23%), scoliosis (17; 16%), and chest wall anomalies (15; 14%). The majority of MD were subclinical, with only 8 patients [8% (6 thoracotomies, 2 thoracoscopies)] requiring intervention. Among patients who underwent thoracotomies (93, 89%), serratus anterior muscle division was the only significant predictor of the development of MD [OR 8.9; 95% CI 2.8-32.6]. CONCLUSION: Musculoskeletal deformities develop in a significant proportion of children following thoracic surgery, but most are subclinical. A muscle-sparing technique decreases the incidence of these deformities. TYPE OF STUDY: Prospective Cohort Study. LEVEL OF EVIDENCE: Level II.

Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia.

BACKGROUND: Beyond its structural role in the skeleton, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders, yet the consequences of an abnormal ECM on cellular communication remains less well understood METHODS: Clinical and radiographic examinations defined the phenotype in this unappreciated bent bone skeletal disorder. Exome analysis identified the genetic alteration, confirmed by Sanger sequencing. Quantitative PCR, western blot analyses, immunohistochemistry, luciferase assay for WNT signaling were employed to determine RNA, proteins levels and localization, and dissect out the underlying cell signaling abnormalities.  Migration and wound healing assays examined cell migration properties. FINDINGS: This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin-mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered ß1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling. INTERPRETATION: This newly described mechanism revealed a LAMA5-ß1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. FUNDING: Supported by NIH awards R01 AR066124, R01 DE019567, R01 HD070394, and U54HG006493, and Czech Republic grants INTER-ACTION LTAUSA19030, V18-08-00567 and GA19-20123S.

Pathogenic variants in EP300 and ANKRD11 in patients with phenotypes overlapping Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS), Rubinstein-Taybi syndrome (RSTS), and KBG syndrome are three distinct developmental human disorders. Variants in seven genes belonging to the cohesin pathway, NIPBL, SMC1A, SMC3, HDAC8, RAD21, ANKRD11, and BRD4, were identified in about 80% of patients with CdLS, suggesting that additional causative genes remain to be discovered. Two genes, CREBBP and EP300, have been associated with RSTS, whereas KBG results from variants in ANKRD11. By exome sequencing, a genetic cause was elucidated in two patients with clinical diagnosis of CdLS but without variants in known CdLS genes. In particular, genetic variants in EP300 and ANKRD11 were identified in the two patients with CdLS. EP300 and ANKRD11 pathogenic variants caused the reduction of the respective proteins suggesting that their low levels contribute to CdLS-like phenotype. These findings highlight the clinical overlap between CdLS, RSTS, and KBG and support the notion that these rare disorders are linked to abnormal chromatin remodeling, which in turn affects the transcriptional machinery.

An apparent new syndrome of extreme short stature, microcephaly, dysmorphic faces, intellectual disability, and a bone dysplasia of unknown etiology.

We report on a 26-year-old male with extreme short stature, microcephaly, macroglossia, other dysmorphic features, severe intellectual disability, and a bone dysplasia. The patient had an extensive genetic and biochemical evaluation that was all normal or noninformative. Recently, the proband died following a period of not eating. He likely had a previously undescribed syndrome of unknown etiology.

Skeletal Dysplasias Caused by Sulfation Defects.

Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children.

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2.

Mutations in TRPV4 are linked to a group of clinically distinct, but also overlapping axonal neuropathies, including Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. The incidence of TRPV4-linked cases ranges from 0 to 7% in overall axonal neuropathy cohorts from European countries and Australia. However, the data from other areas remain largely unknown. In this study, we screened for TRPV4 mutations in a well-characterized USA cohort of 62 unrelated CMT2 patients without mutations in MFN2, GARS, NEFL, and GDAP1. All 15 coding exons of TRPV4 were analyzed by Sanger-sequencing. Clinical features of TRPV4-linked patients were compared with those lacking TRPV4 mutations. We identified two TRPV4 mutations in two patients. A TRPV4-R316C was identified in a patient with family history, while a TRPV4-R269C in an apparently sporadic case. Marked clinical variations were observed in the patients with TRPV4 mutations. Our data suggest that TRPV4-linked CMT2C accounts for a sizable fraction in this USA cohort of CMT2; it has a wide phenotypic spectrum, and vocal cord paralysis, scapular weakness and wasting, skeletal dysplasia, and hearing loss are suggestive signs for TRPV4-linked CMT2C.

Insight into the possible aetiologies of Blount's disease: a systematic review of the literature.

Blount's disease or bowed leg deformity, is a unilateral or bilateral growth deformity of the medial proximal tibia that leads to a tibial varus deformity. A distinction can be made in an early and late onset type. The disease seems to have a predisposition for certain descends. Since the first publication of Blount's disease, different hypotheses on the aetiology are proposed but no consensus exists. The objective of this study is to provide an overview of the available hypotheses on the aetiology of Blount's disease since its first description and assessment of the available level of evidence, the quality of evidence and the occurrence of bias supporting these individual hypotheses. A systematic search according to the PRISMA statement was conducted using PubMed, MEDLINE, EMBASE and the Cochrane Library using a broad combination of terminology to ascertain a complete selection. Proper MESH search criteria were formulated and the bibliographic search was limited to English and Dutch language articles. Articles with no mention of aetiology or a disease related to Blount's were excluded. Level of evidence and types of bias were assessed. Thirty-two articles that discuss the aetiology of Blount's disease were selected. A variety of hypotheses was postulated in these articles with most research in the field of increased mechanical pressure (obesity, early walking age) and race (descend). Blount's disease most likely has a multifactorial origin with influence of genetic and racial predisposition, increased mechanical pressure on the growth plate as a consequence of obesity or early walking age and possibly also nutrition. However, the exact aetiology remains unclear, the probable explanation is that multifactorial factors are all contributing to the development of Blount's disease. Histological research has shown that a disorganization of bone and cartilage structures on the medial side of the proximal tibial physis is present in patients with Blount's disease. Based on the available evidence on the aetiology of Blount's disease, we conclude that it is multifactorial. Most papers focus only on one hypotheses of Blount's disease occurrence and all are characterized as low level of evidence. There seems to be a preference for certain descends. Further research on especially genetic predisposition is needed to provide more insight in this factor of Blount's disease.

Nonossified cervical vertebrae in Wolf-Hirschhorn Syndrome: A case report.

RATIONALE: Wolf-Hirschhorn Syndrome (WHS) is a rare disorder caused by the loss of the distal part of the short arm of chromosome 4, and has various phenotypes depending on the deletion size. Although many articles report on urinary tract malformations or ophthalmologic abnormalities, there are few descriptions of the skeletal anomalies. This is an extremely rare case of cervical dysplasia in WHS. PATIENT CONCERNS: A 24-year-old pregnant woman was transferred to our hospital at 21 gestational weeks for intrauterine growth retardation and oligohydramnios and decided to preserve the pregnancy after evaluation. A female was born at full term by normal vaginal delivery, weighing 1791 g. The patient was suspected to have congenital dysplasia of the cervical vertebrae on the routine newborn chest radiograph, and cervical spine magnetic resonance imaging revealed nonossification of the C3 and C4 vertebral bodies. DIAGNOSIS: The newborn had the "Greek warrior helmet" face typical of WHS. A deletion was detected in the distal portion of the short arm of chromosome 4 (p 16.3) by fluorescence in situ hybridization analysis. INTERVENTIONS: She was hospitalized for nutritional management and congenital anomaly evaluation for a month before being discharged with rehabilitation and antiepileptic drugs. OUTCOMES: The patient has been readmitted with seizure attacks 5 times to date. At one year of age, she still shows severe head lag and feeding problems. Her last weight was below the 3rd centile. LESSONS: Although cervical dysplasia is a rarely reported morphology in WHS, it may provide artefacts for diagnosing WHS as cervical anomalies, unlike facial anomalies or developmental delays, are seldom found in congenital disease.

Physeal bridges: causes, diagnosis, characterization and post-treatment imaging.

The cartilaginous primary physis, or growth plate, at the end of long bones in children allows for longitudinal bone growth. A variety of insults to the physis can lead to physeal bridge formation, which in turn can lead to limb-shortening and angular deformities. This paper begins with a description of the causes, risk factors and mechanisms by which bridges form. Then it reviews the use of imaging in the diagnosis and characterization of bridges and in the evaluation of treatment and post-treatment complications. It is important for radiologists taking care of children to be aware of the indirect and direct imaging findings of physeal bridges to aid in their diagnosis, to be able to characterize bridges as part of preoperative planning, and to know the imaging finding of post-resection complications.

Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.

The dysplastic trochlear sulcus due to the insufficient patellar stress in growing rats.

BACKGROUND: Developmental factors were assumed to be the key factors that influenced the morphology of femoral trochlea. This study investigated the effects of insufficient patellar stress after birth on the morphological development of the femoral trochlea. Effects of insufficient patellar stress on femoral trochlea were investigated using surgical induced patellectomy and patellar dislocation in growing rat model. METHODS: In this study, two experimental groups and one sham group (SG) were established. Thirty-six Wistar rats (female, 28 days of age) were randomly assigned to three groups. The patellectomy group (PG), rats underwent the patellectomy in this group. The dislocation group (DG), rats underwent the surgery-induced patellar dislocation. Histological staining (Safranin-O and fast green), Micro-computed tomographic (Micro-CT) analysis in two experimental endpoints (3, 12 weeks postoperatively) were selected to evaluate morphological changes of the femoral trochlea. RESULTS: Articular cartilage on the trochlear sulcus was remodeled at 3 weeks after the surgery, and degenerated at 12 weeks through the histological staining. The femoral trochlear angle (FTA) did not show a significant difference at 3 week between the experimental groups and the sham group (PG vs SG P = 0.38, DG vs SG p = 0.05), but the FTA was significantly increased in experimental groups at 12 weeks(PG vs SG P = 0.001, DG vs SG p = 0.005). The Bone volume density (BV/TV), Trabecular number (Tb.N) under the trochlea groove were significantly reduced at 3 weeks postoperatively in the experimental groups (PG vs SG p = 0.001, DG vs SG p = 0.002). No significant difference was found in BV/TV and Tb. N among the three groups at 12 weeks postoperatively. CONCLUSION: Surgical induced patellectomy and patellar dislocation leads to the dysplastic trochlear sulcus in growing rats. Besides the bone morphology of trochlear sulcus, the articular cartilage and subchondral trabecula under the trochlear sulcus were remodeled early stage after the surgery.

Slipped capital femoral epiphysis and Blount disease as indicators for early metabolic surgical intervention.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) and Blount disease are strongly associated with pediatric obesity, yet they have only recently been identified as indications for consideration of metabolic and bariatric surgery (MBS). OBJECTIVES: To describe the relationships between pediatric obesity, MBS, SCFE, and Blount disease. SETTING: Nationwide database. METHODS: The national inpatient sample was used to identify patients ≤20 years old with obesity who underwent MBS from 2007 to 2016. Presence of SCFE and Blount disease was similarly extracted. RESULTS: The overall prevalence of SCFE and Blount disease among patients ≤20 years old is .02% for both (14,976, 11,238 patients, respectively) with no statistically significant change over the study period (P = .68, .07, respectively). The rates of SCFE and Blount disease in children with and without obesity are .46% versus .02% and .36% versus .01%, respectively (P < .001 for both). The mean age of patients with SCFE and obesity was 12 years old, while the mean age of those without obesity was 12.2 years old (P = .03). None of the children with obesity and SCFE underwent MBS. Similarly, the mean age of patients with Blount disease and obesity was 12.6 years old, while the mean age of those without obesity was 13.1 years old. Moreover, the mean age of children with Blount disease and obesity who underwent MBS was 16 years old (P < .001). CONCLUSIONS: Orthopedic complications remain a persistent problem in the pediatric population who suffer from obesity. Despite being diagnosed at a young age, patients with SCFE and/or Blount disease are not undergoing MBS until their later adolescent years, potentially leading to unnecessary disease progression or recurrence of disease after orthopedic interventions. Therefore, SCFE and Blount disease should be considered indications for early consideration of MBS in this pediatric population.

RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities.

Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.