Congenital dislocation of the knee in combination with Meyer-Gorlin syndrome: A case report

BACKGROUND: Meyer-Gorlin syndrome is a rare genetic and autosomal recessive disease that is characterized by the classical triad, including, microtia, very small size or complete patellar absence, and nanism. CLINICAL CASE: Herein, presented the first clinical case description of a Russian patient with Meyer-Gorlin syndrome in combination with congenital anterior shin dislocation. The main clinical disease manifestations are characterized by a combination of microtia, patellar pathology, and dwarfism. DISCUSSION: In the practice of pediatric orthopedic surgeons, cases of congenital knee dislocations are extremely rare, especially as part of any syndromes, which cause interest in the presented clinical case publication. Our patient analysis, as well as the patients described in the literature, showed the presence of typical clinical manifestations, which allowed us to suspect the presence of Meyer-Gorlin syndrome during a clinical examination. CONCLUSIONS: This report is the first case of combined congenital knee dislocation and Meyer-Gorlin syndrome with a diagnostic triad (short stature, microtia, and patellar aplasia) in the Russian Federation. Conservative treatment with constant traction and flexion must be carefully performed to avoid complications. Without the effect of conservative therapy, surgical treatment is indicated.

Defining the Spectrum, Treatment and Outcome of Patients With Genetically Confirmed Gorlin Syndrome From the HIT-MED Cohort

Gorlin syndrome is a genetic condition associated with the occurrence of SHH activated medulloblastoma, basal cell carcinoma, macrocephaly and other congenital anomalies. It is caused by heterozygous pathogenic variants in PTCH1 or SUFU. In this study we included 16 patients from the HIT2000, HIT2000interim, I-HIT-MED, observation registry and older registries such as HIT-SKK87, HIT-SKK92 (1987 – 2020) with genetically confirmed Gorlin syndrome, harboring 10 PTCH1 and 6 SUFU mutations. Nine patients presented with desmoplastic medulloblastomas (DMB), 6 with medulloblastomas with extensive nodularity (MBEN) and one patient with classic medulloblastoma (CMB); all tumors affected the cerebellum, vermis or the fourth ventricle. SHH activation was present in all investigated tumors (14/16); DNA methylation analysis (when available) classified 3 tumors as iSHH-I and 4 tumors as iSHH-II. Age at diagnosis ranged from 0.65 to 3.41 years. All but one patient received chemotherapy according to the HIT-SKK protocol. Ten patients were in complete remission after completion of primary therapy; four subsequently presented with PD. No patient received radiotherapy during initial treatment. Five patients acquired additional neoplasms, namely basal cell carcinomas, odontogenic tumors, ovarian fibromas and meningioma. Developmental delay was documented in 5/16 patients. Overall survival (OS) and progression-free survival (PFS) between patients with PTCH1 or SUFU mutations did not differ statistically (10y-OS 90% vs. 100%, p=0.414; 5y-PFS 88.9% ± 10.5% vs. 41.7% ± 22.2%, p=0.139). Comparing the Gorlin patients to all young, SHH activated MBs in the registries (10y-OS 93.3% ± 6.4% vs. 92.5% ± 3.3%, p=0.738; 10y-PFS 64.9%+-16.7% vs. 83.8%+-4.5%, p=0.228) as well as comparing Gorlin M0 SKK-treated patients to all young, SHH activated, M0, SKK-treated MBs in the HIT-MED database did not reveal significantly different clinical outcomes (10y-OS 88.9% ± 10.5% vs. 88% ± 4%, p=0.812; 5y-PFS 87.5% ± 11.7% vs. 77.7% ± 5.1%, p=0.746). Gorlin syndrome should be considered in young children with SHH activated medulloblastoma, especially DMB and MBEN but cannot be ruled out for CMB. Survival did not differ to patients with SHH-activated medulloblastoma with unknown germline status or between PTCH1 and SUFU mutated patients. Additional neoplasms, especially basal cell carcinomas, need to be expected and screened for. Genetic counselling should be provided for families with young medulloblastoma patients with SHH activation.

Novel alterations in IFT172 and KIFAP3 may induce basal cell carcinoma

Background Basal cell carcinoma (BCC) is the most commonly occurring neoplasm in patients with Gorlin syndrome. It is widely accepted that multiple basal cell carcinomas simultaneously develop in middle-aged patients with this syndrome. However, the presence of driver genes other than the PTCH1 in Gorlin syndrome has not been explored. This study aimed to identify common gene mutations other than PTCH1 in simultaneously occurring basal cell carcinomas in patients with Gorlin syndrome via exome sequencing analysis. Methods Next-generation sequencing analysis was performed using four basal cell carcinoma samples, one dental keratinocyte sample, and two epidermoid cyst samples, which were surgically resected from one patient with Gorlin syndrome on the same day. Results Overall, 282 somatic mutations were identified in the neoplasms. No additional somatic mutations in PTCH1, PTCH2, TP53, and SMO were identified. However, enrichment analysis showed that multiple genes, such as IFT172 and KIFAP3, could regulate ciliary functions important for Hedgehog signaling. Conclusion The development of BCCs in patients with Gorlin syndrome may be triggered by mutations that cause substantial dysfunction of cilia.

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) in Children

Introduction: Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is a rare genetic disorder characterised by development of multiple basal cell carcinomas (BCC) at a young age. Case report: A 7 year female child presented with MULTIPLE skin growths on the neck, face and upper chest for 3 years, with prominent forehead and mild non-scarring alopecia. She also had a history of medulloblastoma treated 3 years ago. There was no significant family history. Biopsy from one of the lesions showed basal cell carcinoma (BCC). Discussion: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder caused by mutations in the tumour suppressor patched 1 (PTCH-1) gene. Patients present with both cutaneous and extra-cutaneous manifestations. Multiple basal cell carcinomas (BCCs) are one of the most frequent cutaneous manifestations, occurring on both photo-exposed and non-exposed areas. The commonest extra-cutaneous tumours are medulloblastomas, which are often the first presentation of the disease. There are multiple but no established treatment modalities for the disease.

Biallelic GINS2 variant p.(Arg114Leu) causes Meier-Gorlin syndrome with craniosynostosis

IntroductionReplication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS).ObjectiveIdentification of novel genes associated with MGORS.MethodsExome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, in silico structural protein analysis and modelling in budding yeast.ResultsA novel homozygous missense variant NM_016095.2:c.341G>T, p.(Arg114Leu), in GINS2 was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2–7/GINS) to accurately operate. Interestingly, our patient’s phenotype is strikingly similar to the phenotype of patients with CDC45-related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia.ConclusionGINS2 is a new disease-associated gene, expanding the genetic aetiology of MGORS.