Demir E, Bulut FD, Bilginer-Gürbüz B
… +5 more, Döğen ME, İşlek A, Mermer S, Başer B, Ürel-Demir G
Mol Syndromol
· 2025 Aug · PMID 40771188
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INTRODUCTION: Cholestasis in childhood is a rare clinical condition, yet a definitive diagnosis is crucial for initiating treatment of these curable diseases and preventing related morbidity and mortality. The most commo...INTRODUCTION: Cholestasis in childhood is a rare clinical condition, yet a definitive diagnosis is crucial for initiating treatment of these curable diseases and preventing related morbidity and mortality. The most common cause of infant cholestasis is biliary atresia (25-40%), followed by monogenic cholestatic diseases (25%), metabolic diseases (20%), and cryptogenic cholestasis. This study focuses on assessing the clinical utility of next-generation sequencing (NGS) panels, including clinical exome sequencing and whole exome sequencing, in diagnosing cholestatic diseases when the etiology cannot be elucidated through conventional methods. MATERIALS AND METHODS: We conducted a retrospective examination of pediatric patients who sought care at a single-center pediatric gastroenterology department between August 2020 and March 2022 and were diagnosed with cholestasis. A total of 36 patients underwent a thorough investigation to rule out infectious, toxic, metabolic, structural, chromosomal, and endocrine causes. Patients whose diagnoses were established through traditional investigations were excluded from the study. The remaining 14 patients underwent either whole exome sequencing or targeted NGS methods. RESULTS: A definitive diagnosis was achieved for 12 patients, while 2 patients remained undiagnosed despite comprehensive genetic examinations. The most commonly encountered diseases in this cohort were progressive familial intrahepatic cholestasis, linked to mutations in the , , and genes, as well as Dubin-Johnson syndrome associated with mutations. NGS demonstrated a diagnostic accuracy of 85.7% in patients for whom a diagnosis could not be established through extensive traditional workup. CONCLUSION: NGS emerges as a valuable diagnostic tool in cases of cholestasis where traditional methods fall short in providing a definitive diagnosis. Moreover, our study unveiled three previously undocumented variants in the [c.1165G>C; p.(Ala389Pro) and c.783 + 1G>A] and [c.4246_4247del; p.(Lys1416ValfsTer46)] genes.
Talea A, Bayat S, Khan GS
… +6 more, Pak N, Aziz-Ahari S, Sinaei R, Tavasoli AR, Ashrafi MR, Heidari M
Mol Syndromol
· 2025 Aug · PMID 40771187
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INTRODUCTION: Pseudo-TORCH syndrome, named as such due to the mimicry of intrauterine TORCH infections in the absence of infection, is a neurological disorder presenting primarily with congenital microcephaly, intracrani...INTRODUCTION: Pseudo-TORCH syndrome, named as such due to the mimicry of intrauterine TORCH infections in the absence of infection, is a neurological disorder presenting primarily with congenital microcephaly, intracranial calcifications, simplified gyration and polymicrogyria, and severe developmental delay, which can be attributed to variants in the gene. MCC2 deficiency, a neurometabolic disorder due to impairments in the catabolism of Leucine, with highly variable clinical presentations in addition to landmark metabolic features is put down to variants in gene. CASE PRESENTATION: Known as independent conditions, the intriguing presence of dual manifestations in a 3.5-year-old boy was investigated in the study. The patient was referred to our Myelin Disorders Clinic due to congenital microcephaly, developmental regression, and medication-resistant epilepsy. WES was performed on patient's samples for variant detection and subsequent confirmation. Bioinformatics analysis was performed for prioritization and validation according to the standard criteria. The resultant findings were consequently confirmed in the proband and his parents by Sanger sequencing. WES revealed the presence of two concurrent variants in and on the same chromosome, chromosome 5, both in homozygous state in the proband. Both variants are classified as pathogenic according to ACMG classification system having been previously reported in the literature. CONCLUSION: The two variants observed in our patient, a homozygous missense change and a homozygous deletion interestingly occurring on the same chromosome, lead us to think that either these two conditions may be totally independent of each other, having co-occurred by chance, or there may be an underlying association between the two variants, rendering their co-occurrence as a haplotype more possible.
Dinçsoy Bir F, Uyguner ZO, Karaman B
… +8 more, Baykal C, Büyükbabani N, Tüysüz B, Gedikbaşı A, Uyanık B, Toksoy G, Kara B, Kayserili H
Mol Syndromol
· 2025 Aug · PMID 40771186
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INTRODUCTION: Lipoid proteinosis (LP), a rare autosomal recessive disorder typified by generalized thickening of the skin, mucosa, and certain viscera, is associated with pathogenic variants. Skin lesions like beaded ey...INTRODUCTION: Lipoid proteinosis (LP), a rare autosomal recessive disorder typified by generalized thickening of the skin, mucosa, and certain viscera, is associated with pathogenic variants. Skin lesions like beaded eyelid papules, acneiform scars, wavy, yellow papules and nodules typically appear in early childhood. Some patients may exhibit neurological abnormalities like temporal lobe or hippocampi-amygdala complex calcification, epilepsy, and neuropsychiatric abnormalities. METHODS: We included 15 individuals with LP from 10 unrelated families. The study includes clinical evaluations of family history, radiological findings, histopathological examination of the skin, and genetic investigations. RESULTS: All affected individuals exhibited skin and mucosal lesions. Among the 15 cases, five (33%) showed neurological symptoms, four (26%) presented neuropsychiatric findings, and three (20%) had diabetes mellitus. We observed characteristic intracranial calcifications in all patients with epileptic seizures. Four out of the five cases with epilepsy and intracranial calcifications also had neuropsychiatric findings. All patients with neurological and neuropsychiatric findings had a frame-shift variant, but the same frame-shift variant was not associated with these findings in other individuals. In our study, no patient with variants other than frame-shift variants exhibited neurological or neuropsychiatric findings. Adrenal calcification, which was observed in 1 patient, was not previously linked to LP. CONCLUSION: Our study observed diverse variations in LP cases among the Turkish population, with varying clinical presentation even among individuals with identical variations within the same family. In our series, the lack of correlation between genotype and phenotype makes providing specific genetic counseling to families challenging.
Pasa ID, Frey AC, Ferraciolli SF
… +8 more, Lucato LT, Azevedo Carvalho M, Pagotto MVC, Burlacchini De Carvalho MH, Pulcineli Vieira Francisco R, Honjo RS, Bertola DR, Kim CA
Mol Syndromol
· 2025 Aug · PMID 40771185
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INTRODUCTION: NOTCH3, one of the four mammalian Notch receptors, acts as a transcriptional activator in a variety of tissues. Variants in lead to distinct phenotypes, depending on variant type and location. Truncating v...INTRODUCTION: NOTCH3, one of the four mammalian Notch receptors, acts as a transcriptional activator in a variety of tissues. Variants in lead to distinct phenotypes, depending on variant type and location. Truncating variants in the last exon generate a protein lacking the PEST domain, responsible for degradation, leading to a gain-of-function effect and causing Lateral Meningoceles syndrome (LMS), characterized by dysmorphisms and variable cardiac, skeletal, and connective tissue abnormalities; motor delay may occur, but the cognitive function is usually normal. CASE PRESENTATION: We report the first case of prenatal molecular diagnosis of LMS, which was made using prenatal exome sequencing after an ultrasound with findings of fetal cystic hygroma, mild bilateral ventriculomegaly, and facial dysmorphisms. After birth, magnetic resonance imaging confirmed the presence of lateral meningoceles. A complete clinical evaluation was performed and unexpected biliary anomalies were found. CONCLUSION: The occurrence of biliary anomalies has not been previously reported in LMS but may have biological plausibility. Expression of has been demonstrated in biliary development and is thought to play a role in the differentiation of hepatoblasts into biliary epithelial cells, and also in liver regeneration and repair. We hypothesize that the findings reported here might expand the phenotype of LMS.
Kaymakcalan Celebiler H, Barak T, Rai DK
… +16 more, Kaya I, Erbilgin S, Cikili Uytun M, Oztop D, Gumus H, Per H, Ceylaner S, Bozkurt I, Kontaridis MI, Bilguvar K, Akhun N, Kilincaslan A, Caglayan AO, Erson-Omay EZ, Gunel M, Ercan-Sencicek AG
Mol Syndromol
· 2025 Aug · PMID 40771184
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INTRODUCTION: Mucopolysaccharidosis type IIIB is an autosomal recessive lysosomal disorder caused by variants in the α-n-acetylglucosaminidase () gene. It is a progressive neurodegenerative disorder with no treatment. Pr...INTRODUCTION: Mucopolysaccharidosis type IIIB is an autosomal recessive lysosomal disorder caused by variants in the α-n-acetylglucosaminidase () gene. It is a progressive neurodegenerative disorder with no treatment. Previous enzyme therapies have been unsuccessful. It is important to understand the mechanism of the disease to be able to find new treatments. METHODS: We did whole-exome sequencing and standard Sanger sequencing on 7 cases of four consanguineous families diagnosed with autism spectrum disorder. RESULTS: We identified two recurrent damaging biallelic Asp312Asn and p.Arg234Gly variants in the gene. Structure modeling of these variants suggested that each variant affects the stability of the enzyme and results in a loss of activity. All affected individuals' enzymatic assay in leukocytes clearly showed that α-n-acetylglucosaminidase was completely inactive. Our patients underwent magnetic resonance imaging (MRI), revealing normal findings in two of them despite progressive clinical neurodegenerative symptoms. To our knowledge, these cases represent the second and third instances of normal MRI findings documented in the literature.
Nair P, Bizzari S, Mehawej C
… +8 more, Chouery E, Audi P, Corbani S, Korban R, Mahfoud D, Superti-Furga A, El-Hayek S, Megarbane A
Mol Syndromol
· 2025 Aug · PMID 40771183
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INTRODUCTION: Blended phenotypes resulting from the contribution of two or more genetic variants to the disease of a patient pose a significant diagnostic challenge. Correlating between the phenotypes and the genotypes o...INTRODUCTION: Blended phenotypes resulting from the contribution of two or more genetic variants to the disease of a patient pose a significant diagnostic challenge. Correlating between the phenotypes and the genotypes of the affected patients is difficult in these cases, especially in the absence of a large family segregating the condition. CASE PRESENTATION: We report a child born to consanguineous Syrian parents with a complex phenotype including a skeletal dysplasia, characterized by a small thorax and phalangeal shortening, as well as cardiac anomalies and sensorineural hearing loss. Molecular analysis identified the presence of three potentially disease-causing genetic variants. These include homozygous variants in the and genes, known to be associated with acrocapitofemoral dysplasia (OMIM# 607778) and a form of short-rib thoracic dysplasia (OMIM# 613819), respectively, in addition to a heterozygous variant in the gene, associated with dominant forms of skeletal dysplasia, such as Marshall (OMIM# 154780) and Stickler (OMIM# 608481) syndromes, and hearing loss (OMIM# 618533). CONCLUSION: We propose that the complex phenotype observed in the patient results from the contribution of l three of these variants. This case highlights some of the challenges encountered in the genetic counseling of families with rare genetic conditions.
Doğan Arı AB, Türkyılmaz A, Çiftçi Pınar N
… +4 more, Turhan U, Keçeli AM, Bayrakçı US, Kılıç E
Mol Syndromol
· 2026 Apr · PMID 40734719
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INTRODUCTION: The Crumbs homolog-2 ()-related syndrome is an extremely rare genetic disorder characterized by congenital hydrocephalus, steroid-resistant nephrotic syndrome, and cardiac anomalies. It is caused by biallel...INTRODUCTION: The Crumbs homolog-2 ()-related syndrome is an extremely rare genetic disorder characterized by congenital hydrocephalus, steroid-resistant nephrotic syndrome, and cardiac anomalies. It is caused by biallelic variants in the gene. CASE PRESENTATION: Herein, 2 new patients are presented including congenital hydrocephalus, nephrotic syndrome, scimitar syndrome, and severe cardiac anomalies. -related syndrome was considered with the present clinical findings and whole exome sequencing revealed three novel variants in gene. Microcephaly, ventricular hypertrophy, anomalous pulmonary venous return, pulmonary sequestration, and thymus hypoplasia were presented only in the current patients. Variants in exon 2 (c.335G>A, p.Cys112Tyr) and intron 2 (c.419-2A>G) were reported only in the presented report. In addition, the first likely pathogenic splice-site variant was reported in this report. CONCLUSION: Accurate diagnosis is crucial for increasing clinical awareness and offering genetic counseling to affected families.
Javed Khan M, Abdullah, Khan H
… +10 more, Zaman A, Ahmed S, Iqbal P, Bilal M, Ullah K, Hasni MS, Ullah I, Mis EK, Lakhani SA, Ahmad W
Mol Syndromol
· 2024 Dec · PMID 40657133
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BACKGROUND: Polydactyly is one of the most common hereditary limb malformations, characterized by presence of additional digits in hands and/or feet. It is present either in isolated form or in combination with other fea...BACKGROUND: Polydactyly is one of the most common hereditary limb malformations, characterized by presence of additional digits in hands and/or feet. It is present either in isolated form or in combination with other features. Preaxial polydactyly with extra digit on the outside of the thumb or big toe, and postaxial polydactyly with extra digit on the outside of the little finger or little toe are the two main forms of polydactyly. METHODS AND RESULTS: In the present study, two unrelated consanguineous families segregating PAP in an autosomal recessive manner were investigated. Whole exome sequencing, followed by segregation analysis using Sanger sequencing, revealed a homozygous missense variant [c.1792 G>A; p.(Gly598Arg); NM_005631.5] in the in both families Proteins SMO, PTCH, and GLI act as major components of the Sonic hedgehog pathway, which transmits signals to embryonic cells for cellular differentiation. Homology modeling revealed that the variant in SMO may disrupt proper protein folding and interaction with other molecules. CONCLUSION: Our study has revealed the second direct involvement of a sequence variant in the causing isolated polydactyly. This study will highlight the importance of the inclusion of the gene in screening individuals presenting polydactyly in hands and feet.
Ates K, Ozturk M, Esener Z
… +2 more, Sigirci A, Tekedereli I
Mol Syndromol
· 2026 Apr · PMID 40636265
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INTRODUCTION: Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare multisystemic congenital disorder caused by gene variants. This study aimed to present the results of whole exome sequencing, and describe some rare find...INTRODUCTION: Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare multisystemic congenital disorder caused by gene variants. This study aimed to present the results of whole exome sequencing, and describe some rare findings observed in the proband. CASE PRESENTATION: An 11-year-old boy exhibited hypotonia, poor growth, short stature, and microcephaly. The patient displayed various neurological symptoms, such as developmental delay, seizures, hydrocephalus, and brain abnormalities. He presented with strabismus, urinary problems, and facial dysmorphism. A history of stroke, obsession, insomnia, self-injurious behavior, and hearing loss was also noted. Based on the patient's clinical findings, whole exome sequencing was performed. A novel variant in the gene was identified. This variant was confirmed by Sanger sequencing. Notably, the parents tested normal for the variant. CONCLUSION: This study presents a patient who exhibited a wide range of behavioral abnormalities, stroke, and recurrent urolithiasis - features that are rarely reported in ZTTK syndrome - and includes a review of the literature.
Tabanli G, Hazan F, Ozer G
… +3 more, Koprulu O, Nalbantoglu O, Ozkan B
Mol Syndromol
· 2026 Feb · PMID 40620719
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INTRODUCTION: Opsismodysplasia (OPS) is a rare skeletal dysplasia characterized by delayed bone maturation, distinctive skeletal deformities, and severe growth impairment. Mutations in the gene, particularly homozygous...INTRODUCTION: Opsismodysplasia (OPS) is a rare skeletal dysplasia characterized by delayed bone maturation, distinctive skeletal deformities, and severe growth impairment. Mutations in the gene, particularly homozygous variants, are the primary genetic cause of this condition. While bisphosphonate therapy has shown efficacy in OPS cases with hypophosphatemic rickets, its role in cases without this complication remains unclear. CASE PRESENTATION: A 2-year-and-2-month-old girl with OPS was treated with intravenous pamidronate (0.5 mg/kg/3 months). Initial evaluations showed severe short stature and low bone mineral density (DEXA SDS: -3.16). After three courses of treatment, the patient achieved independent walking, and her DEXA SDS improved to -2.5 over 1 year. DISCUSSION: Pamidronate is effective in treating OPS even in the absence of hypophosphatemic rickets, showing potential as a therapeutic option for this rare condition.
Miyakoshi A, Sueyoshi S, Ijuin A
… +14 more, Hamada H, Nishi M, Tochihara S, Saito M, Ueno H, Kasai M, Saito S, Asano R, Mizushima T, Miyagi E, Murase M, Tanoshima M, Sakakibara H, Hayama T
Mol Syndromol
· 2026 Feb · PMID 40567938
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INTRODUCTION: Turner syndrome is a complicated gonadal insufficiency, infertility, and endocrine disease caused by the partial to complete loss of one X chromosome. Women with Turner syndrome have been reported to show a...INTRODUCTION: Turner syndrome is a complicated gonadal insufficiency, infertility, and endocrine disease caused by the partial to complete loss of one X chromosome. Women with Turner syndrome have been reported to show altered effector T-cell subgroups; however, the relationship between T-cell subgroups and chromosome type remains unknown. METHODS: In this study, we investigated immune abnormalities and karyotypes of Turner syndrome. Using flowcytometry, we examined the T-cell subsets of 20 women with Turner syndrome and 23 women serving as controls (without recurrent pregnancy loss), between July 2021 and June 2022. Background data of the women with Turner syndrome were also collected. RESULTS: Significantly lower levels of helper T-cells 1 and 2 were observed in women with Turner syndrome than in the control group (4.5 ± 2.88 vs. 8.54 ± 4.45, < 0.05, 0.56 ± 0.38 vs. 0.97 ± 0.48, < 0.05, respectively). With respect to karyotypes, deletion of a specific region, pseudoautosomal region 2, which typically escapes X-inactivation, might influence regulatory T cells (Treg) levels as copy number of PAR2 and Treg rate were positively correlated ( = 0.76). CONCLUSION: Individuals with Turner syndrome showed an altered T-cell subset, which might be caused by the deletion of a specific part of the X chromosome, pseudoautosomal region 2. This finding suggests that women with Turner syndrome in a specific karyotype show altered T-cell subsets, and more cases are needed to determine whether these T-cell changes could influence pregnancy outcomes.
Mol Syndromol
· 2026 Feb · PMID 40538467
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INTRODUCTION: Weiss-Kruszka syndrome is a rare, autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the , located at chromosome 9p31.2. Clinically, it is characterized by craniofacial dysmorph...INTRODUCTION: Weiss-Kruszka syndrome is a rare, autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the , located at chromosome 9p31.2. Clinically, it is characterized by craniofacial dysmorphism, global developmental delay, intellectual disability, short stature, congenital anomalies of the heart and brain, and feeding difficulties. The phenotypic spectrum is notably heterogeneous, with variable expressivity and occasional incomplete penetrance. CASE PRESENTATION: Herein, we report a novel de novo heterozygous frameshift variant in , designated c.2924del; p.(Gln975ArgfsTer3) (NM_021224.6), identified in a pediatric patient. CONCLUSION: Importantly, our patient presented with a congenital diaphragmatic hernia - an anomaly not previously described in association with Weiss-Kruszka syndrome. To date, 48 cases have been reported in the literature. Our findings further broaden the phenotypic spectrum linked to variants and emphasize the need for continued clinical and molecular characterization. Through the detailed documentation of this unique case, we aimed to enhance the understanding of the clinical variability and potential comorbidities associated with this emerging syndrome.
Erkan DD, Soğukpınar M, Demir GÜ
… +2 more, Utine GE, Şimşek-Kiper PÖ
Mol Syndromol
· 2025 May · PMID 40475176
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INTRODUCTION: Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive craniofacial features, growth deficiencies, and broad thumbs and halluces. Most diagnoses are made through sequence analysis of the or gene...INTRODUCTION: Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive craniofacial features, growth deficiencies, and broad thumbs and halluces. Most diagnoses are made through sequence analysis of the or genes. Here we focused on two cases diagnosed through chromosomal microarray analysis (CMA), highlighting the significance of genetic variations in RSTS. CASE PRESENTATION: After detailed clinical examinations and genetic evaluations of 2 patients with suspected RSTS, CMA was conducted to identify copy number variations. CMA revealed a 128-kb deletion in the gene in case 1 presenting with dysmorphic features and growth delays. Case 2, a 14-month-old girl with global developmental delay and similar dysmorphic features, was found to have a 1,467-kb deletion encompassing part of the gene. CONCLUSION: Our study underscores the importance of CMA as a critical diagnostic tool for RSTS, particularly in cases where sequence analysis fails to identify pathogenic variants. The identification of significant deletions in the and genes through CMA not only confirms the diagnosis of RSTS but also expands our understanding of the genetic complexity of the syndrome. Since CMA is already included as part of the diagnostic evaluation for RSTS, these findings further emphasize its value in ensuring accurate diagnosis and improving the management of this rare condition.
Mol Syndromol
· 2025 May · PMID 40475175
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INTRODUCTION: Pallister-Hall-Like Syndrome (PHLS) (OMIM #241800), a rare ciliopathy associated with defects in the Sonic Hedgehog pathway, is characterized by postaxial polydactyly, hypothalamic hamartoma, cardiac and sk...INTRODUCTION: Pallister-Hall-Like Syndrome (PHLS) (OMIM #241800), a rare ciliopathy associated with defects in the Sonic Hedgehog pathway, is characterized by postaxial polydactyly, hypothalamic hamartoma, cardiac and skeletal anomalies, and craniofacial dysmorphisms. CASE REPORT: This report describes a 3-day-old girl from a consanguineous family diagnosed with bilateral postaxial polydactyly and facial dysmorphism. Genetic analysis revealed a homozygous pathogenic c.1726 C>T; p.Arg576Trp variant in the gene. CONCLUSION: Consanguineous marriage causes predisposition to ultra-rare conditions. There have been eleven documented cases of this ultra-rare syndrome. To our knowledge, this is the first reported case in Turkiye, enriching our clinical understanding of PHLS.
Kolkıran A, Daşar T, Kablan A
… +1 more, Şimşek-Kiper PÖ
Mol Syndromol
· 2025 May · PMID 40475174
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INTRODUCTION: Kniest dysplasia is a rare skeletal disorder, characterized by mild dysmorphic features, cleft palate, short stature, short limbs, prominent joints, restricted joint mobility, hearing impairment, and ocular...INTRODUCTION: Kniest dysplasia is a rare skeletal disorder, characterized by mild dysmorphic features, cleft palate, short stature, short limbs, prominent joints, restricted joint mobility, hearing impairment, and ocular manifestations such as high-degree myopia, retinal detachment, and cataract. Typical radiological findings include platyspondyly, coronal clefts, and dumbbell-shaped long tubular bones. CASE PRESENTATION: Herein, we report on an 8-month-old boy who was referred to the pediatric genetic department due to narrow thorax and short extremities. He had mild dysmorphic features, cleft palate, narrow thorax, short extremities, and short stature. On radiographies, platyspondyly, hemivertebra, and dumbbell-shaped long tubular bones were detected. Clinical and radiological findings were consistent with Kniest dysplasia. Clinical exome sequencing was performed and revealed a heterozygous, pathogenic c.905C>T (p.Ala302Val) variant in the gene, confirming the initial clinical diagnosis. DISCUSSION: Kniest dysplasia is a very rare skeletal dysplasia, and an accurate clinical diagnosis is important to provide the best possible follow-up.
Mol Syndromol
· 2025 May · PMID 40475173
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INTRODUCTION: Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive condition characterized by early-onset camptodactyly, noninflammatory arthropathy, coxa vara deformity, and, rarely...INTRODUCTION: Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive condition characterized by early-onset camptodactyly, noninflammatory arthropathy, coxa vara deformity, and, rarely, pericardial effusion. The disease gene has been assigned to human chromosome regions 1q25-q31, and truncating mutations have been identified in the - () gene formerly known as megakaryocyte stimulating factor gene. METHODS: A literature review was performed with the findings in patients in terms of CACP syndrome. Also, whole-exome sequencing was performed for all cases. Segregation analyses of the detected variants were performed according to the possibilities. RESULTS: We present 3 Turkish patients with CACP syndrome mimicking juvenile idiopathic arthritis (JIA). All patients were exposed to biologic therapy due to recalcitrant JIA. We have detected two pathogenic PRG4 variants. Case 3 had a novel pathogenic PRG4 variant not reported for the CACP syndrome so far. These two variants cause premature truncation of the protein. A deletion was detected in case 1 in the homozygous state in the gene (NM_005807.6: c.3848del, p.Gly1283GlufsTer6, chr1-186281360-G-). A previously described deletion was detected in case 2 and case 3 in the homozygous state in the gene (NM_005807.6: c.1910_1911delCT, p.Pro637ArgfsTer9, chr1-186276761-CT). CONCLUSION: In the current study, we report three pathogenic PRG4 variants including a novel mutation. We consider that a detailed anamnesis, including kinship and meticulous physical examination of camptodactyly in the absence of inflammatory response, may reveal CACP syndrome masquerading as JIA. The gene analysis presents the early diagnosis for patients and prenatal counseling and preimplantation genetic diagnosis for carrier families.
Minotti C, Graziani L, Micalizzi A
… +8 more, Dentici ML, Capolino R, Sinibaldi L, Lanari V, Dallapiccola B, Novelli G, Novelli A, Digilio MC
Mol Syndromol
· 2025 May · PMID 40475172
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INTRODUCTION: Shashi-Pena syndrome (SHAPNS) is a rare congenital disorder characterized by macrocephaly, delayed psychomotor development with intellectual disability, hypotonia, seizures, episodic hypoglycemia, distinct...INTRODUCTION: Shashi-Pena syndrome (SHAPNS) is a rare congenital disorder characterized by macrocephaly, delayed psychomotor development with intellectual disability, hypotonia, seizures, episodic hypoglycemia, distinct facial features, and glabellar nevus flammeus, caused by heterozygous variants of the gene. CASE PRESENTATION: We report on a 15-year-old patient in care at our hospital since the age of 4 years presenting with minor neurodevelopmental problems, marked postnatal overgrowth without advanced bone age, and dental anomalies. CONCLUSION: Patients described in the literature with SHAPNS are reported indicating a broad spectrum of clinical manifestations. The present patient manifests an atypical presentation of SHAPNS due to a novel heterozygous variant. This study supports the inclusion of SHAPNS in overgrowth disorders with macrocephaly, suggesting the analysis of the gene even in suspected subjects with normal bone age and confirms dental anomalies as a clinical feature of this syndrome. SHAPNS could be inferred even in the absence of developmental delay or epilepsy.
Atasay R, Yilmaz LN, Gulec A
… +7 more, Canpolat M, Per H, Kardas F, Ozsait Selcuk B, Karaman B, Kiraz A, Dundar M
Mol Syndromol
· 2025 May · PMID 40475171
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INTRODUCTION: In consanguineous marriages, different homozygous variants in a single gene may occur in the same family. This may lead to blended phenotypes. This study presents a family in which different rare mechanisms...INTRODUCTION: In consanguineous marriages, different homozygous variants in a single gene may occur in the same family. This may lead to blended phenotypes. This study presents a family in which different rare mechanisms come together as a result of consanguineous marriage. Primary coenzyme Q10 deficiency is a very rare disease that occurs due to homozygous or compound heterozygous variants in the gene. CASE PRESENTATION: A 2-year-old proband with a blended phenotype with sex development disorder and coenzyme Q (CoQ) 10 deficiency has psychomotor retardation, dysmorphic findings, hypotonia, micropenis, and bilateral cryptorchidism. The patient's cytogenetic analysis results were compatible with -positive 46,XX sex reversal disease. In the subsequent whole-exome analysis, a c.437T>G (Phe146Cys) missense homozygous probable pathogenic variant was detected in the 5th exon of the gene (NM_016035) that explains other clinical findings. The brother of the index was previously deceased due to hydrocephalus and had a nonsense homozygous variant c.1051C>T p.(Arg351*) in the 7th exon of the gene (NM_001134830). DISCUSSION: Alterations in exons 5-7 of the COQ4 gene manifest early in life, resulting in neonatal fatality and a more pronounced clinical trajectory. Conversely, mutations occurring in exons 1-4 emerge later and exhibit a less severe clinical progression. Interestingly, the c.437T>G variant within exon 5 of the COQ4 gene induces comparatively milder clinical symptoms, deviating from the documented cases in the literature. To our knowledge, there is no other reported case in the literature with a blended phenotype of a sexual development anomaly and primary CoQ10 deficiency.
Mol Syndromol
· 2025 May · PMID 40475170
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INTRODUCTION: Ellis-Van Creveld syndrome is a rare genetic disorder characterised by skeletal abnormalities, cardiac anomalies, and findings of hidrotic ectodermal dysplasia. Cardiac anomalies are common in this syndrome...INTRODUCTION: Ellis-Van Creveld syndrome is a rare genetic disorder characterised by skeletal abnormalities, cardiac anomalies, and findings of hidrotic ectodermal dysplasia. Cardiac anomalies are common in this syndrome and usually include an atrial septal defect when present. The disorder is caused by homozygous or compound heterozygous pathogenic variants in the and genes. A small number of patients with Ellis-Van Creveld syndrome have also been found to have copy number variants associated with these two genes. CASE PRESENTATION: A 13-year-old girl patient was referred to the paediatric genetic department with short stature, short extremities, operated post-axial polydactyly, nail hypoplasia, and severe mitral valve insufficiency. Chromosomal microarray analysis identified a 45 kb homozygous deletion encompassing exons 3-11 of the gene at 4p16.2. CONCLUSION: Herein, we present a case with an intragenic deletion of the gene and expand the clinical and genetic spectrum of Ellis-Van Creveld syndrome.