PUF60 loss-of-function with normal cognition should be considered in the differential diagnosis of Klippel-Feil syndrome.

Klippel-Feil syndrome (KFS) has a genetically heterogeneous phenotype with six known genes, exhibiting both autosomal dominant and autosomal recessive inheritance patterns. PUF60 is a nucleic acid-binding protein, which is involved in a number of nuclear processes, including pre-mRNA splicing, apoptosis, and transcription regulation. Pathogenic variants in this gene have been described in Verheij syndrome due to either 8q24.3 microdeletion or PUF60 single-nucleotide variants. PUF60-associated conditions usually include intellectual disability, among other findings, some overlapping KFS; however, PUF60 is not classically referred to as a KFS gene. Here, we describe a 6-year-old female patient with clinically diagnosed KFS and normal cognition, who harbors a heterozygous de novo variant in the PUF60 gene (c.1179del, p.Ile394Serfs*7). This is a novel frameshift variant, which is predicted to result in a premature stop codon. Clinically, our patient demonstrates a pattern of malformations that matches reported cases of PUF60 variants; however, unlike most others, she has no clear learning difficulties. In light of these findings, we propose that PUF60 should be considered in the differential diagnosis of KFS and that normal cognition should not exclude its testing.

Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.

Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive disorder caused by biallelic pathogenic variants in MYO18B and comprises, in addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial dysmorphism, and short stature. We aim to outline the natural history of KFS4 and provide an updated description of its clinical, radiological, laboratory, and molecular findings. We comprehensively analyzed the medical records of 6 Saudi and 1 American patients (including 5 previously unpublished cases) with a molecularly confirmed diagnosis of KFS4. All patients had myopathy of varying severity that followed a slowly progressive or non-progressive course, affecting primarily the proximal musculature of the lower limb although hand involvement with distal arthrogryposis and abnormal interphalangeal creases was also observed. KFA and characteristic dysmorphic features, including ptosis and bulbous nose, were observed in all but two patients. The causal MYO18B variants were a founder NM_032608.5:c.6905C>A; p.(Ser2302*) variant in the Saudi patients (P1-P6) and a novel MYO18B homozygous variant (c.6660_6670del;p.[Arg2220Serfs*74]) in the American Caucasian patient (P7). We report the phenotypic and genetic findings in seven patients with KFS4. We describe the natural history of this disease, confirm myopathy as a universal feature and describe its pattern and progression, and note interesting differences between the phenotypes observed in patients with KFA and those without.

Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity.

The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo-vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel-Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro-caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X-ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family-based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico-thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240-4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo-axoidal malformation compromising spinal cord integrity. This distinctive mutation-specific pattern of malformation differs from Klippel-Feil syndrome and broadens the current classification, defining a sub-type of RIPPLY2-related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo-auriculo-vertebral spectrum disorder.

Skeletal malformations of Meox1-deficient zebrafish resemble human Klippel-Feil syndrome.

Klippel-Feil syndrome is a congenital vertebral anomaly, which is characterised by the fusion of at least two cervical vertebrae and a clinically broad set of symptoms, including congenital scoliosis and elevated scapula (Sprengel's deformity). Klippel-Feil syndrome is associated with mutations in MEOX1. The zebrafish mutant choker (cho) carries a mutation in its orthologue, meox1. Although zebrafish is being increasingly employed as fidelitous models of human spinal disease, the vertebral column of Meox1-deficient fish has not been assessed for defects. Here, we describe the skeletal defects of meox1cho mutant zebrafish utilising alizarin red to stain bones and chemical maceration of soft tissue to detect fusions in an unbiased manner. Obtained data reveal that meox1cho mutants feature aspects of a number of described symptoms of patients who suffer from Klippel-Feil syndrome and have mutations in MEOX1. These include vertebral fusion, congenital scoliosis and an asymmetry of the pectoral girdle, which resembles Sprengel's deformity. Thus, the meox1cho mutant zebrafish may serve as a useful tool to study the pathogenesis of the symptoms associated with Klippel-Feil syndrome.

Klippel-Feil syndrome and levo-looped transposition of the great arteries.

Klippel-Feil syndrome is a skeletal disorder characterised by low hairline and a short neck due to abnormal fusion of two or more cervical vertebrae. Although congenital heart and lung defects are infrequent, some abnormalities such as cor triatriatum, coarctation of the aorta, total anomalous pulmonary venous connection, or lung agenesis have been reported. The challenge of recognising Klippel-Feil syndrome lies in the fact that there is an association of this syndrome with other significant conditions such as skeletal, genitourinary, neurological, ear, and some cardiac defects. We report a Klippel-Feil syndrome type III 14-year-old patient with a levo-looped transposition of the great arteries. In addition, the patient had agenesis of the left upper-lung lobe.

Molecular landscape of congenital vertebral malformations: recent discoveries and future directions.

Vertebral malformations (VMs) pose a significant global health problem, causing chronic pain and disability. Vertebral defects occur as isolated conditions or within the spectrum of various congenital disorders, such as Klippel-Feil syndrome, congenital scoliosis, spondylocostal dysostosis, sacral agenesis, and neural tube defects. Although both genetic abnormalities and environmental factors can contribute to abnormal vertebral development, our knowledge on molecular mechanisms of numerous VMs is still limited. Furthermore, there is a lack of resource that consolidates the current knowledge in this field. In this pioneering review, we provide a comprehensive analysis of the latest research on the molecular basis of VMs and the association of the VMs-related causative genes with bone developmental signaling pathways. Our study identifies 118 genes linked to VMs, with 98 genes involved in biological pathways crucial for the formation of the vertebral column. Overall, the review summarizes the current knowledge on VM genetics, and provides new insights into potential involvement of biological pathways in VM pathogenesis. We also present an overview of available data regarding the role of epigenetic and environmental factors in VMs. We identify areas where knowledge is lacking, such as precise molecular mechanisms in which specific genes contribute to the development of VMs. Finally, we propose future research avenues that could address knowledge gaps.

Klippel-Feil syndrome associated with congenital cervical dislocation: report of an autopsy case.

Klippel-Feil syndrome is an uncommon congenital anomaly that is characterized by abnormal fusion of the cervical vertebrae and occasionally accompanied by various anomalies of other bones and internal organs. We report the autopsy case of a 5-year-old girl with this syndrome ssociated with congenital cervical dislocation, with special reference to the pathological findings of the vertebral column and spinal cord. Principal anomalies of the cranio-spinal axis were as follows: partial defect of the clivus, scoliosis, hypoplasia of the whole cervical vertebrae, anterior dislocation of C7 with S-shaped deformity of the spinal canal, fusion of the spinous processes of the cervical and thoracic vertebrae, fusion of the vertebral bodies of C6 and C7 with collapse of C7, and spina bifida occulta of L5 and S1. In addition to these skeletal anomalies, subarachnoid vascular malformation in the medulla oblongata, a bronchogenic cyst in the posterior mediastinum, anomalous lobation of the lungs, and the mobile cecum were found at autopsy. The cervical cord showed an increase of the antero-posterior diameter, multifocal spongy changes of the white matter, and partial branching or duplication of the central canal. The brain showed features of anoxic encephalopathy. The partial defect of the clivus, C7 dislocation, and various lesions of the medulla oblongata and cervical cord were interpreted as integral components of, or lesions closely associated with, Klippel-Feil syndrome.

Type III Klippel-Feil syndrome: case report and review of associated craniofacial anomalies.

Klippel-Feil syndrome (KFS) is a complex syndrome of osseous and visceral anomalies that include the classical clinical triad of short neck, limitation of head and neck movements and low posterior hairline. It may also be associated with anomalies of the genitourinary, musculoskeletal, neurologic and cardiac systems. We report a case of type III KFS with associated rib anomalies such as cervical rib, fusion and bifid ribs, scoliosis and fused crossed renal ectopia. The aim of this paper was to summarize all craniofacial anomalies that occur in association with KFS, so that clinicians would be aware of them during diagnosis and treatment planning.

The VANGL1 P384R variant cause both neural tube defect and Klippel-Feil syndrome.

BACKGROUND: Neural tube defect (NTD) is a common birth defect causing much death in the world. Variants in VANGL1 lead to NTD and caudal regression syndrome. NTD displays a complex phenotype encompassing both genetic and environmental factors. METHODS: The fetus was diagnosed by prenatal ultrasound examination. Postnatal CT and autopsy were performed. Genetic testing was conducted in the family and Sanger sequencing was validated. Multiple prediction soft-wares were used to predict the pathogenicity of the variant. RESULTS: The VANGL1 gene variant c.1151C>G (P384R) was detected in a fetus diagnosed with tethered spinal cord and sacrococcygeal lipoma. The VANGL1 variant c.1151C>G (P384R) was reported in a Klippel-Feil syndrome patient. The VANGL1 variant was validated in the trio-family but the mother showed no abnormalities. CONCLUSION: Overall, this study presents fetal NTD caused by the same VANGL1 variant found in a Klippel-Feil syndrome patient with complete clinical information of prenatal ultrasound, postnatal CT, and genetic results as early as 25 GW. Our study not only expands the VANGL1 mutational spectrum but also sheds light on the important role of the VANGL1 P384R variant in human development.

Split medulla in association with multiple closed neural tube defects.

PURPOSE: We describe the case of a patient with a split medulla associated with multiple closed neural tube defects. CASE REPORT: This 13-year-old female initially presented to our service at just over a year of age for neck abnormalities and a congenital midline occipital dermal sinus. MRI and CT scans showed the presence of multiple cervical vertebral segmentation abnormalities, a bony spur at the level of the craniocervical junction, split medulla, split cervical spinal cord, and a midline occipital dermal sinus. Since the patient's neurological course had remained stable during follow-up for over 11 years, the only surgical procedure undertaken was excision of the dermal sinus to prevent infection. CONCLUSIONS: The constellation of abnormalities indicates that the notochord was split early during gestation, both rostral and caudal to the cervicomedullary junction. Surgical intervention to treat the other malformations needs to be considered only if the patient develops a progressive neurological deficit.

Rare association of Klippel Feil syndrome with cleft palate and congenital cardiac deformities: a case report.

Klippel Feil Syndrome comprises of three characteristic deformities of short neck, a low dorsal hair line and restricted neck mobility. This is a case report of Klippel Feil Syndrome and its rare association with cleft of hard and soft palate, coarctation of aorta, dextrocardia and situs inversus. An interdisciplinary approach towards the management included cardiac surgery, cleft repair and complete oral rehabilitation of the patient. Presently the patient is undergoing speech therapy and is under regular follow up.

Klippel-Feil syndrome: a review of the literature.

Klippel-Feil syndrome is a congenital defect in the formation or segmentation of the cervical spine. A wide spectrum of associated anomalies may be present. This heterogeneity has complicated clarification of the genetic causes and management of patient's with congenital vertebral fusion. In this review, we focussed on clinical heterogeneity; radiographic abnormalities and genetic etiology in Klippel-Feil syndrome. We insist on comprehensive evaluation and delineation of diagnostic and prognostic classes.

Klippel-Feil Syndrome with Cervical Diastematomyelia in an Adult with Extensive Cervicothoracic Fusions: Case Report and Review of the Literature.

Split cord malformation (SCM) is a developmental disorder that is usually symptomatic and diagnosed in childhood. The majority of these lesions are in the thoracic and lumbar spine, with only 1%-3% of cases found in the cervical spine. This is a case report of a 55-year-old female patient with an unremarkable medical history who presented with neck pain. Upon workup, she was found to have extensive developmental anomalies throughout her cervical and thoracic spine, including an incidentally found type 2 SCM and multiple autofused vertebrae. There are only 6 similar studies published in the literature. There was extensive facet degeneration in her cervical spine, which was suspected to be the etiology of her neck pain. This case illustrates the rare finding of asymptomatic adult cervical SCM and the likely significance of her autofused vertebrae causing accelerated symptomatic facet spondylosis.

Rheumatoid arthritis, Klippel-Feil syndrome and Pott's disease in Cardinal Carlo de' Medici (1595-1666).

OBJECTIVE: A paleopathological study was carried out on the she skeletal remains of Cardinal Carlo de' Medici (1595-1666), son of the Grand Duke Ferdinando I (1549-1609) and Cristina from Lorraine (1565-1636), to investigate the articular pathology described in the archival sources. METHODS: The skeletal remains of Carlo, buried in the Basilica of San Lorenzo in Florence, have been exhumed and submitted to macroscopic and radiological examination. RESULTS: The skeleton of Carlo revealed a concentration of different severe pathologies. Ankylosis of the cervical column, associated with other facial and spine anomalies suggests a diagnosis of congenital disease: the Klippel-Feil syndrome. In addition, the cervical segment presents the results of the tuberculosis (Pott's disease) from which the Cardinal suffered in his infancy. The post-cranial skeleton shows an ankylosing disease, mainly symmetrical and extremely severe, involving the large as well as small articulations, and characterized by massive joint fusion, that totally disabled the Cardinal in his last years of life. CONCLUSIONS: The final diagnosis suggests an advanced, ankylosing stage of rheumatoid arthritis.

Crisis resource management of the airway in a patient with Klippel-Feil syndrome, congenital deafness, and aortic dissection.

Klippel-Feil syndrome is a visually arresting deformity wherein severe restriction of cervical motion predicts a difficult airway. Even minor distraction of the neck risks cervical spine or neurologic injury, so regional techniques, awake fiberoptic intubation, or awake tracheostomy are recommended anesthetic approaches. We present a case of aortic dissection in a Klippel-Feil syndrome patient for whom congenital bilateral deafness, coupled with the urgency of the surgery, mitigated against the recommended first-choice techniques. Using anesthesia crisis resource management methods, a multi-member team rehearsed predefined roles and then managed the airway via inhaled induction of anesthesia, followed by flexible fiberoptic intubation.

Klippel-Feil syndrome in association with posterior fossa dermoid tumour.

BACKGROUND: Klippel-Feil syndrome (KFS) is characterized by specific congenital anomalies of segmentation of the cervical spine. On the other hand, dermoid tumour is a rare entity accounting for 0.04-0.7% of all intracranial tumours and the most common location is in the posterior fossa, at or near the midline. CASE DESCRIPTION: A new case with the association of KFS and the posterior fossa dermoid tumour is presented with complaints of progressive headache, occipital lump, and short neck. Plain radiography and 3D computed tomography (CT) of the craniovertebral region revealed a central occipital hole as well as fusion of the C4-7 vertebrae. CT and magnetic resonance imaging (MRI) of the brain demonstrated a well circumscribed midline cystic mass without contrast enhancement in the posterior fossa compressing the vermis and cerebellum. A suboccipital craniectomy was done and dermoid tumour with dermal sinus was removed totally after the opening of the dura mater. Pathological examination confirmed that the mass was a dermoid tumour consisting of stratified squamous epithelium, hair, keratin and sebaceous glands. Control MRI showed no evidence of recurrence and the patient was asymptomatic. CONCLUSION: The experience prompted me to review reports in the literature since 1936 of posterior fossa dermoid tumour associated with KFS. From my analysis, I highlight early diagnosis and an appropriate surgery to prevent complications such as neural compression and bacterial or aseptic meningitis through the rupture site or dermal sinus in cases of KFS associated with for dermoid tumours of the posterior fossa.

Expanding the clinical history associated with syndromic Klippel-Feil: A unique case of comorbidity with medulloblastoma.

Klippel-Feil syndrome (KFS) is an exceedingly rare constitutional disorder in which a paucity of knowledge exists about the disease and its associated morbidity and mortality. We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitutional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTer16 and p.Arg2220SerfsTer74) each encoding a premature stop of translation in MYO18B, consistent with a diagnosis of KFS. We did not identify any somatic variants of known relevance or disease-relevant therapeutic targets in the tumor. The somatic copy number profile was suggestive of Group 3γ medulloblastoma. Relative to pediatric brain tumors, medulloblastoma, particularly, Group 3, had increased gene expression of MYO18B. In summary, coexisting constitutional and somatic diagnoses in this patient enabled the elucidation of the genetic etiology of KFS and provided support for the role of MYO18B in tumor suppression.

Vertebral artery dissection in a patient with Wildervanck syndrome.

Vertebral artery dissection as a cause of stroke is rarely reported in children. The association between vertebral artery dissection and Klippel-Feil syndrome is also very rare. We report on a case of vertebral artery dissection with posterior circulation involvement in a child with Klippel-Feil syndrome after a hard physical-training lesson. She was also diagnosed with Wildervanck syndrome, with additional clinical findings. Vertebral artery dissection should be considered in patients with Klippel-Feil syndrome who present with acute-onset neurologic signs. Movements such as hyperextension with rotation of the neck should be avoided in these cases.

Fusion of cervical vertebrae from a basal archosauromorph from the Middle Triassic Denwa Formation, Satpura Gondwana Basin, India.

This report describes two adjacent, longitudinally-fused anterior cervical vertebrae from a basal archosauromorph. The specimen was collected from the Denwa Formation, Satpura Gondwana Basin, India. The differential diagnosis of the fusion includes genetic or environmentally-mediated congenital malformations, nonspecific spondyloarthopathy, and various infectious agents. These observations represent the first published recognition of archosauromorph vertebral pathology from specimens that were discovered in India. The observations affirm that basal archosauromorphs suffered from disorders that have been observed in later dinosaurs and modern-day vertebrates. Considering the process of orderly differential diagnosis is an important aspect of understanding lesions of ancient bones.