The Stone Inscription of Tsogt Taij (Čoɣtu Tayiǰi)

This chapter provides an English translation of the stone inscription of Čoγ‎tu Tayiǰi. Čoγ‎tu Tayiǰi was a Mongolian prince over the Khalkha people in what today is the country of Mongolia. He lived in the waning years of the Yuan Dynasty (1260–1635) and died patronizing Sakyapa Buddhism in war against rising Gèlukpa hegemony under the Fifth Dalai Lama and his benefactor, Güüshi Khan of the Oirad Qoshod clan. The inscription, said to have been composed by him upon ascending to the summit of a lofty mountain in the Khangai range during a hunting expedition, is an elegy of the Buddhist world, expressing love and longing for a paternal aunt who recently had moved to a faraway land. The poem is said to have been taken down by a page named Erke who was with him at the time (in the late summer of 1621) and then inscribed in stone a few years later (in 1624) by another page, this one named Dayičing, and a knight named Güyeng.

Birthweight in offspring and cardiovascular mortality in their parents, aunts and uncles: a family-based cohort study of 1.35 million births

Background A link between suboptimal fetal growth and higher risk of cardiovascular disease (CVD) is well documented. It has been difficult to assess the contribution of environmental versus genetic factors to the association, as these factors are closely connected in nuclear families. We investigated the association between offspring birthweight and CVD mortality in parents, aunts and uncles, and examined whether these associations are explained by CVD risk factors. Methods We linked Norwegian data from the Medical Birth Registry, the Cause of Death Registry and cardiovascular surveys. A total of 1 353 956 births (1967–2012) were linked to parents and one maternal and one paternal aunt/uncle. Offspring birthweight and CVD mortality association among all relationships was assessed by hazard ratios (HR) from Cox regressions. The influence of CVD risk factors on the associations was examined in a subgroup. Results Offspring birthweight was inversely associated with CVD mortality among parents and aunts/uncles. HR of CVD mortality for one standard deviation (SD) increase in offspring birthweight was 0.72 (0.69–0.75) in mothers and 0.89 (0.86–0.92) in fathers. In aunts/uncles, the HRs were between 0.90 (0.86–0.95) and 0.93 (0.91–0.95). Adjustment for CVD risk factors in a subgroup attenuated all the associations. Conclusions Birthweight was associated with increased risk of CVD in parents and in aunts/uncles. These associations were largely explained by CVD risk factors. Our findings suggest that associations between offspring birthweight and CVD in adult relatives involve both behavioural variables (especially smoking) and shared genetics relating to established CVD risk factors.

Unusual AIP mutation and phenocopy in the family of a young patient with acromegalic gigantism

Summary Early-onset acromegaly causing gigantism is often associated with aryl-hydrocarbon-interacting receptor protein (AIP) mutation, especially if there is a positive family history. A15y male presented with tiredness and visual problems. He was 201 cm tall with a span of 217 cm. He had typical facial features of acromegaly, elevated IGF-1, secondary hypogonadism and a large macroadenoma. His paternal aunt had a history of acromegaly presenting at the age of 35 years. Following transsphenoidal surgery, his IGF-1 normalized and clinical symptoms improved. He was found to have a novel AIP mutation destroying the stop codon c.991T>C; p.*331R. Unexpectedly, his father and paternal aunt were negative for this mutation while his mother and older sister were unaffected carriers, suggesting that his aunt represents a phenocopy. Learning points: Typical presentation for a patient with AIP mutation with excess growth and eunuchoid proportions. Unusual, previously not described AIP variant with loss of the stop codon. Phenocopy may occur in families with a disease-causing germline mutation.

Diffuse Gastric Ganglioneuromatosis: Novel Presentation of PTEN Hamartoma Syndrome—Case Report and Review of Gastric Ganglioneuromatous Proliferations and a Novel PTEN Gene Mutation

Gastrointestinal ganglioneuromatous proliferations are rare, most often found in the colon, and are three types: polypoid ganglioneuromas, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. We present a case of diffuse ganglioneuromatosis in the posterior gastric wall in a nine-year-old female. To our knowledge, this is the first reported case of diffuse ganglioneuromatosis located in the stomach. Only six cases of gastric ganglioneuromatous proliferations have previously been reported, two in English and none were diffuse ganglioneuromatosis. A diagnosis of diffuse ganglioneuromatosis is relevant for patient care because, unlike sporadic polypoid ganglioneuromas or ganglioneuromatous polyposis, most are syndromic. Diffuse ganglioneuromatosis is commonly associated with neurofibromatosis type 1, multiple endocrine neoplasia type 2b, and Cowden Syndrome, one of the phenotypes of PTEN hamartoma tumor syndrome. The patient had the noted gastric diffuse ganglioneuromatosis, as well as other major and minor criteria for Cowden syndrome. Genetic testing revealed a novel frameshift mutation in the PTEN gene in the patient, her father, paternal aunt, and the aunt’s son who is a paternal first cousin of the patient.

Glioblastoma in a Patient with a Hereditary Cancer Syndrome

A 68-year-old Caucasian male presented to emergency with a spontaneous sudden onset headache localized behind the left eye. Pain was severe and associated with vomiting, agitation, anxiety, memory loss, and word-finding difficulty. There was no preceding trauma and no meningeal symptoms. Further history was significant for mitral valve repair, atrial fibrillation treated with coumadin, colorectal cancer treated with right-sided hemicolectomy 17 years prior, and multiple skin tumors, which included squamous cell and basal cell carcinomas of his face and ears. Family history was significant for colon cancer in his father (at age 50), a sister (at age 40), and a niece (at age 38), as well as primary brain cancer in his paternal aunt.

A Large Mennonite Family with a Novel K570N TERT Gene Mutation: Association with a Clinical Spectrum of Bone Marrow Failure, Acute Myeloid Leukemia, and Acute Liver Failure.

Mutations in telomere repair complex genes TERT (encoding telomerase reverse transcriptase) and TERC (telomerase RNA component) are associated with bone marrow failure, especially acquired aplastic anemia and dyskeratosis congenita. Low telomerase activity leads to short telomeres of leukocytes, predisposing highly proliferative tissues such as the bone marrow to early senescence and exhaustion of the stem cell compartment. Telomere repair gene mutations have been suggested to result in disease anticipation, defined as earlier and/or worsening clinical manifestations in successive generations. We have identified a six-generation pedigree in a large Mennonite family carrying a novel TERT mutation (K570N), which localizes in the catalytic domain with reverse transcriptase activity (RT domain). The index patient is a 26 year old male dairy farmer with a ten-year history of severe aplastic anemia (5% bone marrow cellularity) unresponsive to immunosuppression. A long history of hematologic diseases was well known and named in the family--the patient’s paternal great-great-grandmother had died of a severe blood disorder at age 65 years. However, the great-grandmother and the grandfather had never presented any hematological disease. The patient’s father had myelodysplastic syndrome at age 33 years, evolving to acute myeloid leukemia and death due to failure to recover blood counts after chemotherapy. One of the proband’s paternal aunts had aplastic anemia develop when she was a young woman and has been transfusion-independent for decades in response to chronic androgen therapy. A second proband’s paternal aunt underwent a liver transplant at age 20 for submassive hepatic necrosis with fibrosis. A third proband’s paternal aunt has macrocytosis only at age 47. Two sisters (ages 21 and 23) also have macrocytosis in the absence of other hematological abnormality, and two other sisters are healthy. Genetic analysis showed that TERT K570N mutation is present in the patient’s paternal (including grandfather, three aunts and two affected sisters) but not maternal relatives (making his father an obligatory carrier). The patient’s oldest of three sons, now age four years, has the mutation but is asymptomatic. There was no nail dystrophy, leukoplakia or skin hyperpigmentation in any of the TERT K570N carriers; although the index patient and some of his relatives showed early graying of hair, this characteristic did not track with the mutation. Telomere shortening of leukocytes, as measured by Flow-FISH, tracked to the mutation in three generations analyzed, being shortest in the proband and in his aunt with marrow failure. Mutagenized TERT vectors transfected into telomerase-deficient VA13 cell lines yielded no telomerase activity using the telomeric repeat amplification protocol (TRAP) assay, whereas when wild-type TERT vectors were co-transfected, telomerase activity was approximately half of wild-type transfected only, indicating haploinsufficiency as a mechanism of telomere shortening. Our results confirm the association between aplastic anemia and TERT mutations. The pattern of hematologic disease in this kindred does not support disease anticipation in TERT mutations. Most remarkably, there is a likely relationship between a telomerase gene mutation and hematological malignancy and severe liver disease.

Factor VII Padua 2: another factor VII abnormality with defective ox brain thromboplastin activation and a complex hereditary pattern

A new factor VII abnormality is presented. The propositus was a 9-yr- old child who presented a mild bleeding tendency characterized by epistaxis and easy bruising. The parents were not consanguineous, but they came from the same area. The laboratory features were mild prolongation of prothrombin time and P.P. test and normal partial thromboplastin and Stypven cephalin clotting times. The Thrombotest was moderately prolonged. Factor VII was 40%-50% of normal using rabbit or human brain thromboplastin, but only 13%-24% using ox brain thromboplastin. Factor VII cross-reacting material (CRM) was about 50% of normal. The father, a paternal aunt, and a paternal cousin showed similar clinical and laboratory findings. The brother of the propositus, the mother, and other members of her family showed about 50% factor VII activity and CRM and were considered to be heterozygotes for true factor VII deficiency. Similar findings were also present in the father and in the brother of the affected cousin. The defect in the propositus seems to consist of a double heterozygosity between abnormal factor VII and heterozygous factor VII true deficiency. The factor VII abnormality appears to consist of abnormal reactivity toward ox brain tissue thromboplastins and appears to be different from previously described factor VII abnormalities. The name factor VII Paudua2 is proposed for this condition.