Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

BACKGROUND: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

Perampanel markedly improved clinical seizures in a patient with a Rett-like phenotype and 960-kb deletion on chromosome 9q34.11 including the STXBP1.

Intractable epilepsy was successfully controlled using perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor antagonist, in a 27-year-old woman who presented with a Rett syndrome-like phenotype and novel 960-kb deletion involving syntaxin-binding protein 1 on chromosome 9q34.11. Perampanel may be an effective antiepileptic drug for intractable epilepsy associated with STXBP1 mutations.

[A case of recurrence of breast cancer 36 years after mastectomy treated with endocrine and chemotherapy].

In 2001, a 72-year-old woman, who had undergone left mastectomy for breast carcinoma 36 years ago, was admitted because of dysphagia. Chest CT showed pleural effusion in the right side and no tumor in the breast. Chest drainage was performed. Cytology of chest effusion revealed adenocarcinoma. A high serum CA15-3 level was noted. She was diagnosed with a pleural recurrence of breast cancer, so administration of CAF agents (4 courses) was started. Pleural effusion was improved and the serum CA15-3 level was reduced. She was then clinically followed on medication with oral anastrozole (AI). After 4 years, progression of disease was noted. The serum CA15-3 level was elevated. A tumor measuring 3 cm was confirmed on the right chest wall. The tumor was removed under local anesthesia and pathological findings showed invasive ductal carcinoma expressing estrogen receptor. Chemotherapy with taxane had to be withdrawn because of its side effect. Administration of S-1 was then started. The serum CA15-3 level was gradually elevated. Thereafter, the regimen was switched to combined S-1 and toremifene citrate. The serum CA15-3 level was reduced and sustained for several months. However, she died of multiple organ metastasis in 2008.

[Chemotherapy-naïve advanced malignant fibrohistiocytoma presenting IVC syndrome case report].

The case was a 77-year-old male with swelling of his right leg. Physical examination revealed an ill-defined mass at RLQ. Computed tomography (CT) and 3 dimensional CT showed an 8-cm tumor on the IVC, partially replacing iliac vessels and invading the psoas muscle. A diagnosis of malignant fibrohistiocytoma was made by pathological examination of biopsied specimens at exploratory laparotomy. Five courses of combination chemotherapy of ifosfamide (IFM) and doxorubicin (DXR) resulted in PR. Edema of the lower leg and hydronephrosis were both alleviated. Another 5 courses of chemotherapy with epirubicin and IFM were added. PR lasted 2 years, though the patient succumbed to the disease in 2 years and 8 months.

[A case of small cell carcinoma of the esophagus with SIADH].

The patient was a 63-year-old male admitted for further evaluation of the bleeding esophageal tumor. Endoscopic biopsy revealed small cell carcinoma. CT scan of the abdomen demonstrated nodular enlargement at the celiac axis. Under diagnosis of small cell carcinoma of the esophagus at Stage IVa, neoadjuvant chemotherapy with FP (5-FU+CDDP) was given. Immediately after fluid load, levels of serum sodium decreased to 117 mEq/L and persisted during chemotherapy treatment despite aggressive corrections. Response and shrinkage of the distant nodal metastases were confirmed, and an esophagectomy was conducted. Pathological examination with IHC demonstrated positive staining for CD56, NSE and synaptophysin but negative for ADH. Lymph node and liver metastases recurred. Progression of the disease again triggered hyponatremia.

Successful low-dose chemotherapy using vinblastine and methotrexate for the treatment of an ileoanal pouch mesenteric desmoid tumor: report of a case.

The purpose of this report was to describe the first known case of ileoanal pouch salvage by a low-dose regimen of vinblastine and methotrexate chemotherapy for the treatment of desmoid tumor arising from the mesentery of the ileoanal pouch in a patient who had undergone ileal pouch-anal anastomosis for familial adenomatous polyposis. Mesenteric desmoid tumor involving the ileoanal pouch in a 28-year-old female was treated with vinblastine and methotrexate biweekly for 12 months and monthly for 12 months in an outpatient unit. The desmoid tumor response to the treatment was assessed at routine intervals by physical examination and magnetic resonance imaging. Desmoid tumor was successfully treated with a low-dose regimen of vinblastine and methotrexate chemotherapy without significant side effects, and function of the ileoanal pouch was fully preserved. Magnetic resonance imaging showed a decrease in desmoid tumor size and cellularity, and changes consistent with fibrosis. This is a unique case highlighting the possibility of ileoanal pouch salvage by low-dose combination chemotherapy using vinblastine and methotrexate in a familial adenomatous polyposis patient with mesenteric desmoid tumor.