Intractable & Rare Diseases Research Vol. 6(2017) No. 3

Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare disease linked to the loss of function of either TTC37 or SKIV2L, two components of the SKI complex. It is characterized by a combination of 9 signs (intractable diarrhea, hair abnormalities, facial dysmorphism, immune abnormalities, IUGR/SGA, liver abnormalities, skin abnormalities, congenital heart defect and platelet abnormalities). We present a comprehensive review of the management of SD/THE and tested therapeutic regimens. A review of the literature was conducted in May 2017: 29 articles and 2 abstracts were included describing a total of 80 patients, of which 40 presented with mutations of TTC37, 14 of SKIV2L. Parenteral nutrition was used in the management of 83% of the patients and weaned in 44% (mean duration of 14.97 months). Immunoglobulins were used in 33 patients, but data on efficacy was reported for 6 patients with a diminution of infection (n = 3) or diarrhea reduction (n = 2). Antibiotics (n = 11) provided no efficacy. Steroids (n = 17) and immunosuppressant drugs (n = 13) were used with little efficacy and mostly in patients with IBD-like SD/THE. Hematopoietic stem cell transplantation (HSCT) was performed in 4 patients: 2 died, for one it corrected the immune defects but not the other features and for the last one, it provided only a partial improvement. Finally, no specific diet was effective except for some contradictory reports for elemental formula. In conclusion, the management of SD/THE mainly involves parenteral nutrition and immunoglobulin supplementation. Antibiotics, steroids, immunosuppressants, and HSCT are not recommended as principle treatments since there is no evidence of efficacy.

Fetal pleural effusion is a rare abnormality that results from accumulation of fluid in the chest cavity. It can be classified as primary fetal hydrothorax and secondary fetal hydrothorax. The underlying causes of pleural effusion are still unknown, and the current treatment strategies are mainly based on symptoms. The prognosis of fetal pleural effusion varies significantly, ranging from spontaneous resolution to perinatal death. Recent advances in prenatal diagnostic methods and treatment such as thoracoamniotic shunting have significantly improved the survival rates for patients with or without hydrops.

Antiphospholipid (aPL) antibodies are antibodies specific for anionic phospholipids. They are immunoglobulins that attack phospholipids, phospholipid-binding proteins, or phospholipid-protein complexes and are detected in anticardiolipin and lupus anticoagulant assays. aPL antibodies are often associated with antiphospholipid syndrome (APS) which can be idiopathic or from secondary causes such as systemic lupus erythematosus (SLE), infection or drugs. They have also been shown to be associated with Pulmonary Hypertension. We conducted a review of the literature that included all articles on PubMed with keywords 'antiphospholipid antibody' and 'pulmonary hypertension' between January 1980 and July 2017 and identified 217 articles. A total of 47 articles were found to be relevant to the topic and included as references. We ascertained that aPL antibodies have been implicated in the development of both idiopathic pulmonary arterial hypertension (PAH) and PAH associated with connective tissue disease (CTD). aPL antibodies were also noted to be associated with left-sided valvular heart disease that can lead to pulmonary venous hypertension (PVH). Patients with anitiphospholipid antibody syndrome (Diagnostic criteria incudes +aPL antibodies) were noted to have a high risk of developing chronic thromboembolic pulmonary hypertension (CTEPH). A recent study also found a positive association of aPL antibodies with ILD and PH in patients with systemic sclerosis. While association between autoimmune thyroid disease and PH (Group V PH), and autoimmune thyroid disease and aPL antibodies is established, no studies linked these three phenomena together. Thus, aPL antibodies had an association with all WHO groups of Pulmonary hypertension (PH). In this review article, we study the association and discuss the need for screening for PH in patients with positive aPL antibodies.

Recurrent bile duct stones is the most common complication after gallstone surgery and the incidence is about 4-24%. Sphincter of Oddi laxity will lead to duodenal content flow into the bile or pancreatic duct. Patients with recurrent bile duct stones and Oddis sphincter laxity were intractable. Here we sought to present the possible and helpful surgical treatments for such patients. Prospective randomized clinical trial are needed for evaluating the outcome of surgical treatments.

The calcium/calmodulin-dependent serine protein kinase gene (CASK) mutations are associated with various neurological disorders; a syndrome of intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID with/without nystagmus, epileptic encephalopathy, and autistic spectrum disorder (ASD). Next generation sequencing was performed to elucidate genetic causes in siblings exhibiting developmental disorders, and a novel CASK mutation, c.1424G>T (p.Ser475Ile), was detected in a male patient with ID, ASD, and microcephaly. Radiological examination of his brain showed no structural abnormality. The identified mutation was shared with the healthy mother and a younger sister exhibiting ASD. Although the mother showed a skewed X-chromosome inactivation (XCI) pattern, the sister showed a paradoxical XCI pattern. This would explain why this sister possessed a normal intellectual level, but showed the same ASD symptoms as the affected brother. A novel CASK mutation was identified in two siblings with ID and/or ASD, suggesting a relationship between the CASK mutation and ASD. Recently performed large molecular cohorts for patients with developmental disorders suggest that CASK is one of the genes related to developmental disorders. For better understanding of genotype-phenotype correlation in ASD cases with CASK mutations, more information should be accumulated.

Mucopolysaccharidoses (MPS) types I, II and VI are associated with deficiencies in alpha-L-iduronidase, iduronate-2-sulfatase and N-acetylgalactosamine-4-sulfatase, respectively, and generally involve progressive and multi-systemic clinical manifestations. Enzyme replacement therapy (ERT) appears to be reasonably well tolerated. The aim of this study was to examine clinical and diagnostic findings of a series of pediatric and adult MPS patients, and assess the safety and efficacy of ERT in children and adults with MPS type I, II and VI. Pediatric and adult patients were treated weekly with 1 mg/kg recombinant human N-acetylgalactosamine-4-sulphatase (rhASB), 0.45 mg/kg alpha-L-iduronidase, or 0.5 mg/kg iduronate-2-sulfatase. Clinical and biochemical parameters with ERT were evaluated for a mean duration of 5 years. Mantel-Haenszel risk ratios and associated 95% confidence intervals (CIs) were calculated for rates of death among different types of enzyme replacement therapies (ERTs). Twenty-seven patients (mean ages – pediatric: 6.8 years; adult: 29 years) were included. ERT was found to be consistently well tolerated and effective in attenuating symptoms, but did not prevent the progression of the disease or reduce mortality rates. Our findings demonstrated that early diagnosis and initiation of ERT are critical for improvements in patient-important outcomes and quality of life, although disease progression and mortality rates remain high.

Cystic fibrosis (CF) is a multisystem autosomal recessive genetic disorder with significant advances in early diagnosis and treatment in the last decade. It is important to provide updated information regarding these changing demographics as they also reflect a considerable improvement in survival. We analyzed the National Inpatient Sample Database (NIS) in the United States for all patients in which CF was the primary discharge diagnosis (ICD-9: 277.0-277.09) from 2003 to 2013 to evaluate the rate of hospitalizations and determine the cost and mortality associated with CF along with other epidemiological findings. The statistical significance of the difference in the number of hospital discharges, lengths of stays and associated hospital costs over the study period was calculated. In 2003, there were 8,328 hospital discharges with the principal discharge diagnosis of CF in the United States, which increased to 12,590 discharges in 2013 (p < 0.001). The mean hospital charges increased by 57.64% from US$ 60,051 in 2003 to US$ 94,664 in 2013. The aggregate cost of hospital visits increased by 138.31% from US$ 500,105,727 to US$ 1,191,819,760. In the same time, the mortality decreased by 49.3 %. The number of inpatient discharges related to CF has increased from 2003 to 2013. This is due to increased life expectancy of CF patients, resulting in increased disease prevalence. There has been a significant increase in the mean and aggregate cost associated with CF admissions. Over the last decade, many advances have been made in the diagnosis and treatment of CF, consequentially leading to a significant transformation in the epidemiology and demographics of this chronic disease. Rising hospital costs associated with the care of CF patients necessitates future studies analyzing the diagnostic modalities, algorithms and treatment practices of physician's treating CF patients.

Omohyoid muscle syndrome (OMS) is a rare disease characterized as a protruding lateral neck mass feature during swallowing. Because there is a 5 cm scar after traditionally surgery, we designed a laparoscopic surgery procedure to meet the cosmetic needs of patients. From the year 2006 to 2016, there were 3 patients diagnosed as omohyoid muscle syndrome that underwent laparoscopic surgery. Operative and postoperative follow-up data were summarized. Average surgery time was 35 ± 13 min. Average blood loss was 3 ± 1 mL. No case converted to open surgery. No major vessel or nerve damage complications occurred. After the surgery, the neck mass completely disappeared during swallowing, and there were no operative scars on the neck. All patients were discharged within 2 days. During the follow-up of a year, no recurrence occurred. In conclusion, the endoscopic procedure is suitable for OMS. It's a safe, effective and cosmetic surgery.

Ectopic pheochromocytoma (EP) is considered as pheochromocytoma located at extra-adrenal site. Surgical removal is believed to be the best choice for treatment of pheochromocytoma. We present a series EP resected by laparoscopic approach (LEP) and confirm its feasibility. We retrospectively reviewed clinical data of 4 patients underwent laparoscopic resection of LEP (periaortocaval EP, n = 1; retroperitoneal EP, n = 2; bladder EP, n = 1), which was collected and analyzed retrospectively in Zhejiang Provincial People's Hospital. The tumors were all successfully resected by laparoscopic approach, and there was no one conversed to open surgery or needing blood transfusion. Laparoscopic resection is a feasible and safe choice for EP.

A 26-year-old male patient presented with features suggestive of osteomyelitis involving the entire left femur, hip joint and knee joint. Culture from the debrided tissue grew Acinetobacter spp. and he was treated with sensitivity based antibiotics but the symptoms did not resolve. The synovial biopsy showed multinucleated giant cells and acid fast bacilli on Ziehl Neelsen stain. Cartridge based nucleic acid amplification test (GeneXpert) was negative. The Mycobacteria growth indicator tube culture was found to be positive for Mycobacterium abscessus. The patient was started on imipenem, amikacin and macrolide based therapy. There was partial response initially but the patient worsened again. A girdle stone arthroplasty with cemented nail (with tobramycin) insertion after debridement of the infected tissue was done. Potassium hydroxide (KOH) mount from the debridement sample was found to be positive for aseptate hyphae suggestive of mucormycosis. He was treated with liposomal amphotericin B. He was evaluated for immunodeficiency in view of multiple atypical infections and was found to have a low CD4 count. The patient was discharged on amikacin, azithromycin, trimethoprim-sulfamethoxazole and posaconazole. Follow up showed considerable resolution both clinically and radiologically. To our knowledge, this is the first reported case of osteomyelitis with co-infection of Acinetobacter spp., M. abscessus and mucormycetes. We report this case to highlight the possibility of multiple rare infections in patients with immunodeficiency. Also, atypical complicated bone infections, such as Mycobacterium abscessus and Mucormycetes might require combined medical and surgical treatment.

Ameloblastoma is a rare low-grade odontogenic tumor of epithelial origin. The World Health Organization (WHO) has defined malignant ameloblastoma (MA) as a histologically benign-appearing ameloblastoma that has metastasized. Treatment of the primary ameloblastoma usually consists of radical excision of the tumor and adjuvant radiotherapy. Chemotherapy should be used to treat metastases due to its indolent clinical course. Presented here is the case of a 43-year-old woman who was admitted to a hospital in 2006 with a large mass involving the neck and left mandible. The mass had formed over years and had been neglected. The woman was diagnosed with a primary ameloblastoma of the mandible. Surgical resection was performed, followed by adjuvant radiotherapy. In September 2016, she was admitted again, and the findings were consistent with metastases of the previously identified ameloblastoma to the lungs. The patient was evaluated for further chemotherapy with 6 cycles of cisplatin pegylated filgrastim. The current case represents the classical course of a rare disease, which in this instance involved the common presentation of MA. This case is a valid incidence of MA based on the typical histology, findings from a lung biopsy, the immunohistochemical profile of the tumor, the typical clinical features, and a history of a previous primary disease.

Lymphatic filariasis is caused by nematodes Wuchereria bancrofti, Brugia malayi and Brugia timori. Lymphatic filariasis is a spectrum of illness and can manifest as, asymptomatic microfilaraemia, acute lymphatic filariasis (lymphangitis and lymphoedema), chronic lymphoedema, elephantiasis, hydrocele, tropical pulmonary eosinophilia and some systemic manifestations which involves joint, heart, kidney, nerve, etc. We here present a case of huge splenomegaly caused by lymphatic filariasis which is a rare presentation and only few cases had been reported in the world literature so far. After treatment of filariasis spleen size was reduced dramatically and patient is doing well even after 6 months of follow up after therapy.

According to the literature, sigmoid volvulus typically develops in patients of an older age with co-morbidities such as a psychiatric illness or a bed-bound chronic illness. Recent reports suggest that it should also be considered in young individuals without any preceding medical history. Abdominal roentgenography is a cheap and effective diagnostic modality that can avoid a delay in diagnosis. The treatment of colonic volvulus remains controversial and relies upon the procedure selected and the most appropriate therapeutic approach in terms of the clinical status of the patient, the location of the problem, the suspected existence or identification of peritonitis, bowel viability, and the expertise of the surgical team. Presented here are four cases of young male patients with sigmoid volvulus. All of the patients were diagnosed radiologically prior to surgical intervention. Two of the patients initially underwent an endoscopic procedure that succeeded in one and that failed in the other. Three of the patients underwent a laparotomy.

A 41-year-old female presented with a pedunculated mass in the upper esophagus and bilateral lymphadenopathy. Biopsies suggested a neuroendocrine tumor, possibly carcinoid, and ensuing imaging revealed cervical lymph node metastases. The esophageal mass was removed endoscopically and discovered by pathologists to closely resemble medullary thyroid carcinoma (MTC) on immunohistochemistry staining. Following surgery, further work up demonstrated very high serum calcitonin levels, suggestive of medullary thyroid carcinoma, however the thyroid gland was normal on ultrasound. The patient underwent a neck dissection to remove the lymph node metastases and subsequently her calcitonin levels dropped to 0 ng/mL, indicating remission. It appears that the primary tumor was not in the thyroid, but in the cervical esophagus. The thyroid has appeared normal on multiple ultrasounds without any detectable nodules or masses. This is quite a unique case because this patient presented with a tumor resembling medullary carcinoma of the thyroid that presented as a pedunculated mass in the cervical esophagus. The actual final diagnosis of this mass in the cervical esophagus was neuroendocrine tumor (NET), consistent with a carcinoid tumor, not ectopic MTC. This case report highlights that calcitonin-secreting tumors outside the thyroid should not lead to erroneous recommendations for thyroidectomy.

A young adult man with 4-years history of lepromatous leprosy (received irregularly multidrug therapy) presented with two and half years history of symptoms suggestive of chronic erythema nodosum leprosum (ENL), initially responded to steroids and thalidomide, but later on failed. During the last 2-months, he developed fever, vomiting, and subsequently altered sensorium. On evaluation, he had hepatosplenomegaly, hyponatremia, hyperferritinemia, hemophagocytosis in bone marrow aspiration, lobular panniculitis in skin biopsy, and multiple parenchymal nodules in chest imaging. Hence diagnosis of ENL with hemophagocytic lymphohistiocytic (HLH) syndrome was established and treatment with dexamethasone (10 mg/m²) started. During hospitalization, he developed sinus bradycardia, QT prolongations, recurrent ventricular tachycardia, and moderate systolic dysfunction. The cardiac complications recovered using a temporary pacemaker and were presumed to be due to micronodular cardiac deposition of ENL. This case iterates that ENL can present with varied presentations like asymptomatic lung nodules and storming cardiac complications. More importantly leprosy, ENL, and HLH are a continuum of manifestations of the same agent-host interactions.

This corrects the article "Novel SLC16A2 mutations in patients with Allan-Herndon-Dudley syndrome" in volume 5 on page 214-215.

Keiko Shimojima, Koichi Maruyama, Masahiro Kikuchi, Ayako Imai, Ken Inoue, and Toshiyuki Yamamoto (2016). Novel SLC16A2 mutations in patients with Allan-Herndon-Dudley syndrome. Intractable Rare Dis Res. 5:214-217.

On page 214, abstract line 10, p.(Gly221Ser) should be p.(Gly147Arg). On page 215, 2.2. Genetic examination lines 12-13, c.661G>A [p.(Gly221Ser)] should be c.439G>A [p.(Gly147Arg)].