Severe Hemophilia a and Moyamoya (SHAM) Syndrome Caused By Xq28 Microdeletion without Risk of Thrombosis: A Case Report

Introduction

Hemophilia A is a rare bleeding disorder characterized by factor VIII deficiency, which leads to prolonged bleeding and other related symptoms. Moyamoya disease is a rare condition characterized by multiple blockages in the cerebral circulation, resulting in a distinctive network of collateral vessels that can be present with recurring episodes of cerebral ischemia and is complicated by thrombosis.

Severe Hemophilia A and Moyamoya (SHAM) syndrome is a relatively new rare genetic condition. It is caused by Xq28 microdeletions, which are deletions in a specific region of the X chromosome, encompassing the F8 and BRCC3 genes. This case report described SHAM syndrome in two pediatric siblings without identified risk factors for thrombosis, treated with Emicizumab, a monoclonal antibody used to treat Hemophilia A.

Case report:

Patient 1

A 6-year-old boy with Down syndrome, congenital heart disease (including a small ventricular septal defect), a history of post-patent ductus arteriosus closure with a device during infancy, resolved gastroesophageal reflux and resolved laryngomalacia. He was initially presented at the age of four months with epistaxis and subsequently diagnosed as a case of severe hemophilia A and was started on with recombinant Factor VIII prophylaxis therapy.

Follow-up genetic testing by whole exome sequencing identified a hemizygous interstitial deletion at Xq28 (~62 kilobases [kb] in size), encompassing exon 1 of the F8 gene, as well as the complete genes FUNDC2, CMC4, MTCP1, and exons 1-5 of the BRCC3 gene. These findings confirmed the diagnosis of SHAM syndrome. Notably, the patient's latest CT scan revealed no signs of brain insult and normal skeletal survey, and they proceeded for MRI/MRA but with difficulties.

At age of 18 months, the decision was made to start him on anemicizumab loading dose followed by a maintenance dose of 6 mg/kg every four weeks. This decision was made due to the difficulty of IV line and the presence of inhibitors. Despite the initial challenges, the treatment was successful, with the patient's annual bleeding rate (ABR) dropping from 4 to zero, and no side effects were observed.

Patient 2:

Brother 2 is a 3-year-old boy diagnosed with severe hemophilia A. Due to his family history, his bleeding profile was tested early, revealing prolonged coagulation parameters and a low factor VIII level, which has been less than 1% since birth. He also has congenital heart disease, a small ventricular septal defect (not on treatment), uncontrolled bronchial asthma, and scoliosis. He has experienced spontaneous bleeding episodes, requiring prophylaxis with recombinant factor VIII since he was nine months old. Despite consistent prophylaxis, the patient persisted in experiencing recurrent self-limiting epistaxis and frequent breakthrough traumatic bleeding, resulting in a difficult IV cannula, prompting the initiation of emicizumab therapy on the same regimen as his brother. Despite experiencing persistent mild neutropenia reaching 1.2, he showed no other adverse effects from emicizumab and remained stable. Given the patient's family history and clinical presentation, he underwent genetic testing using chromosomal microarray analysis, which revealed a pathogenic copy number loss of 65 kb at Xq28. Consistent with Brother 1's case, this variant results in the complete loss of the OMIM genes FUNDC2, CMC4, and MTCP1; exon 1 of the F8 gene; and exons 1-5 of the BRCC3 gene. This finding confirms the SHAM syndrome diagnosis.

Initially, the ABR was 3, which then decreased to 0.5. A skeletal survey yielded normal results apart of scoliosis.Overall, the patient is doing well and has not shown any signs of thrombosisor brain insult. Both patients' parents are not related, and they have two elder male siblings who are normal.

Regular follow-ups were scheduled to monitor treatment efficacy and overall health for both patients with a multidisciplinary team (hematologist, geneticist, cardiologist, pulmonologist, orthopedic) . Their quality of life has improved, hospital visits have lessened, apart from their asthma attacks, and the parents' satisfaction has increased.

Conclusion:

Our patients are a rare case with Xq28 microdeletion encompassing the F8 gene. Emicizumab treatment was effective, with no observed risk of side effects. This study emphasizes the importance of early genetic testing for better clinical management and patient monitoring.

No relevant conflicts of interest to declare.