Aug 2026· American Journal of Medical Genetics. Part A· 0 citations· 23 references
Medicine
TL;DR
It is demonstrated that YVS has a highly characteristic and recognizable phenotype, with digital abnormalities representing the most diagnostically valuable finding warranting FIG4 sequencing.
Abstract
Yunis-Varon syndrome (YVS; MIM: 216340) is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in FIG4, characterized by skeletal, neurological, and ectodermal abnormalities. This systematic review analyzes 15 cases with biallelic FIG4 variants and a clinical diagnosis of YVS to refine the clinical phenotype and diagnostic criteria, as well as a further 25 clinical diagnoses without FIG4 variants. Three "hand and feet" criteria were developed, identifying 1: bilateral and symmetrical thumb aphalangia with or without first metacarpal aplasia or hypoplasia, 2: aphalangia of at least one other upper limb digit, and 3: hallux absence or proximal positioning consistent with aplastic or hypoplastic first metatarsal. These limb abnormalities serve as highly characteristic diagnostic features. We also show that a significant proportion of cases without molecular confirmation in the literature are likely to be misdiagnosed. All molecularly confirmed cases with published photographs or radiographs exhibited a characteristic "1-2 digital pattern" with the first digit being most severely affected, followed by the second digit, and the remaining digits being more mildly affected. Additional consistent features included microretrognathia, short philtrum with everted upper lip, sparse hair and brows, wide fontanelles, and variable brain abnormalities including ventriculomegaly and cortical malformations. Clavicular hypoplasia or aplasia was common, but less consistent a finding than the digital abnormalities described. Median age at last follow-up or death was 669 days. This review demonstrates that YVS has a highly characteristic and recognizable phenotype, with digital abnormalities representing the most diagnostically valuable finding warranting FIG4 sequencing.
Schwartz-Jampel Syndrome (SJS) is a rare autosomal recessive disorder characterised by myotonia, craniofacial dysmorphism and skeletal dysplasia, resulting from pathogenic variants in Heparan Sulfate Proteoglycan 2 (HSPG2). Pathogenic variants disrupt perlecan function, resulting in abnormal cartilage development and impaired neuromuscular transmission. A three-year and fivemonth-old male presented with blepharophimosis, generalised muscle stiffness, delayed motor milestones and gait abnormality. Electromyography demonstrated continuous spontaneous myotonic discharges. Radiographs revealed metaphyseal dysplasia with epiphyseal abnormalities. Molecular testing identified three heterozygous HSPG2 variants with parental carrier status, consistent with compound heterozygosity. Carbamazepine and structured rehabilitation were administered. Follow-up demonstrated reduction in myotonia, improved gait parameters and decreased fall frequency. In early-onset myotonic disorders, SJS should be considered with characteristic craniofacial and skeletal features. Symptomatic treatment with sodium-channel–blocking agents and multidisciplinary rehabilitation may confer functional benefit.
Komal J Rathod, P. S. Parihar, Ramesh Chaple et al.· Journal of Clinical and Diag...· 0 citations
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor-predisposition syndrome caused by pathogenic variants in the NF1 gene and characterized by significant phenotypic variability. Pigmentary and cutaneous lesions, such as café-au-lait macules, skinfold freckling, and dermal or plexiform neurofibromas, occur in nearly all affected individuals and form the core diagnostic criteria. These features often provide the earliest indication of NF1 before neurological, skeletal, or ophthalmological complications. Complete cutaneous phenotypes are less frequently documented when extracutaneous manifestations predominate, and pigmentary-pilar markers of subclinical internal disease are often overlooked.
A 20-year-old man was evaluated after experiencing four years of progressive axial cervical pain following a motorcycle accident, accompanied by radicular pain and gait disturbance that necessitated wheelchair use. Imaging revealed severe destruction of the C5-C6 vertebral bodies with kyphotic deformity, subsequently identified as compressive myelopathy secondary to NF1. Skeletal and surgical findings are reported separately. The patient's father, two paternal aunts, and paternal grandmother exhibited cutaneous lesions consistent with neurofibromas across three generations, supporting autosomal dominant inheritance. Independent of the skeletal assessment, a systematic mucocutaneous examination identified multiple café-au-lait macules on the trunk, axilla, thigh, and leg; bilateral axillary and inguinal freckling extending atypically to the neck and palmoplantar surfaces; and hyperpigmented, hypertrichotic patches on the right arm and left hand. The family reported a dorsal patch with hypertrichosis that could not be examined due to cervical immobilization. The patient fulfilled four of the seven revised 2021 NF1 criteria (≥6 café-au-lait macules, axillary/inguinal freckling, ≥2 cutaneous neurofibromas, and an affected first-degree relative), exceeding the two required for diagnosis.
Although a multigenerational cutaneous phenotype was present, the diagnosis was established only after four years of orthopedic and neurological symptoms. This case illustrates how systemic complications of NF1 can delay recognition of a diagnosis that could have been identified earlier through a structured skin examination. Freckling extending beyond the classic axillary and inguinal distribution to the neck and palmoplantar surfaces warrants further characterization. Hyperpigmentation and hypertrichosis overlying the skin are recognized markers of underlying plexiform neurofibroma, which often remains occult and carries a lifelong risk of malignant transformation. In this patient, imaging did not confirm these markers, and targeted MRI of the affected limbs is recommended next. The unexamined dorsal lesion and the three-generation pedigree further inform follow-up priorities and genetic counseling.
The complete mucocutaneous phenotype in this patient was sufficient to establish the diagnosis of NF1, despite the initial presentation with a rare and severe skeletal complication. This case underscores the importance of systematic skin examination and suggests that pigmentary-pilar markers may indicate clinically silent internal disease.
Ana Sophia Ortiz Robles, Flavio Antonio Sarabia Alba, Francisco Alejandro Sarabia Alba· International Journal of Med...· 0 citations
Background: Cohen syndrome is a rare autosomal recessive developmental disorder with various clinical manifestations. These include failure to thrive, hypotonia, intellectual
disability, pigmentary retinopathy, myopia, nyctalopia, microphthalmia, acquired microcephaly, truncal obesity, joint hypermobility, intermittent neutropenia, and many other
less frequent or subtle features. The condition is associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, on chromosome 8. Over 150 mutations in
VPS13B have been reported in more than 200 patients with Cohen syndrome. Causative mutations include nonsense, missense, indeland splice-site variants.
Case Presentation: Two cases of Cohen syndrome that lack the typical myopic component and instead exhibit significant hyperopia: +5.00-1.00*175 Right Eye (RE) and +5.00-
1.50*180 Left Eye (LE) for the first case, and +3.00-1.00*180 (RE), +3.00-1.00*10 (LE) for her sister. Comprehensive ophthalmologic tests were performed, including fundus
photography, optic coherence tomography (OCT), and electroretinography (ERG). Relevant literature was reviewed and correlated with their clinical features and genetic findings. This observation underscores the importance of reevaluating the ophthalmic manifestations and genetic spectrum of Cohen syndrome.
Conclusions: To our knowledge, this is the first report of Cohen syndrome cases presenting with hyperopia rather than myopia. Further studies are necessary to establish the full range of ophthalmic presentations and their genetic implications in Cohen syndrome.
Sumayah A. Alzahrani, Khalid F. Alharbi, Rafaa Babgi· Case Reports in Ophthalmolog...· 0 citations
We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected.
Irene Ambrosetti, Flavia Palombo, Diego D'Angeli et al.· International Journal of Mol...· 0 citations
Rationale: Hypohidrotic ectodermal dysplasia (HED) is a rare inherited disorder characterized by hypohidrosis, hypotrichosis, and hypodontia. Most cases are caused by mutations in the EDA signaling pathway, whereas TP63-related HED is extremely rare. To our knowledge, this is the first reported case of HED caused by a novel TP63 mutation presenting with a pathological femoral neck fracture. Patient concerns: A 31-year-old woman presented with progressive left hip pain and inability to bear weight for 2 weeks without a history of trauma. She had a lifelong history of hypohidrosis, heat intolerance, sparse hair, hypodontia, dry skin, and nail abnormalities. Diagnoses: Physical examination and radiographs revealed a displaced femoral neck fracture. Laboratory investigations demonstrated severe anemia, end-stage renal disease, secondary hyperparathyroidism, vitamin D deficiency, and osteoporosis. Whole exome sequencing identified a previously unreported heterozygous TP63 frameshift mutation (NM_001114982, c.1092_1093del, p.Asn364fs). Based on the clinical manifestations, laboratory findings, and genetic testing results, the patient was diagnosed with HED, pathological femoral neck fracture, end-stage renal disease, secondary hyperparathyroidism, osteoporosis, and severe anemia. Interventions: After correction of anemia and electrolyte imbalance by hemodialysis and blood transfusion, the patient underwent uncemented bipolar hemiarthroplasty. Outcomes: She began partial weight-bearing ambulation on postoperative day 3 and was discharged on postoperative day 6. Lessons: This case expands the mutational and phenotypic spectrum of TP63-associated HED by describing a previously unreported mutation presenting with a pathological femoral neck fracture and end-stage renal disease. It highlights the importance of early diagnosis, comprehensive genetic testing, multidisciplinary management, and regular follow-up for patients with HED.
Guanghua Liang, Xiang-Ning Meng, Talante Juma et al.· Medicine· 0 citations
Williams syndrome is a rare multisystem genetic disorder caused by a microdeletion at chromosome 7q11.23 involving the elastin (ELN) gene. It commonly presents with cardiovascular abnormalities, developmental delay, connective tissue defects, and characteristic facial dysmorphism. We report a 9-month-old male infant with recurrent respiratory tract infections, developmental delay, and failure to thrive. Bronchoscopy showed mild tracheomalacia and bilateral bronchomalacia, and he had previously undergone right inguinal hernioplasty. On examination, characteristic dysmorphic facial features raised suspicion for Williams syndrome. Echocardiography revealed severe discrete coarctation of the aorta with concentric left ventricular hypertrophy and bilateral superior vena cava. During balloon coarctoplasty, right renal artery stenosis was identified, representing a rare vascular association. Genetic studies confirmed the diagnosis of Williams syndrome with deletion involving chromosome 7q11.23. This case highlights the importance of careful clinical evaluation and genetic confirmation in children with syndromic facies and vascular anomalies for early diagnosis and appropriate multidisciplinary management of Williams syndrome.
Madamshetty Niharika, Vaishnavi R. Kendre, P. Inamdar et al.· International Journal of Con...· 0 citations
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