Paternal Aunt Research Articles

GH1 C.291 + 34G>C in a Growth Hormone Deficient Pedigree

Background: Heterozygous loss of function mutations in GH1 are a cause of autosomal dominant isolated growth hormone deficiency (GHD) or IGHD type II. However, this condition is rare and a genotype/phenotype association is often based on single case or pedigree reports. Clinical Case: The male proband was born at 38 weeks following an uncomplicated pregnancy, birthweight 2585 gm (˗1.3SD), length 43 cm (˗2.7SD). At 20 months old: length ˗3.2SD, weight/length 16%. Peak growth hormone (GH) levels 4.42 ng/mL and 3.2 ng/mL following clonidine and arginine stimulation, respectively; cortrosyn-stimulated cortisol was 41.4 mcg/dL. Prolactin was 61.2 ng/mL (reference range 2.6 to 13.1 ng/mL); T4 and TSH levels were normal. Magnetic resonance imaging showed a flattened anterior pituitary gland, consistent with empty sella, with normal bright spot. He has had an intermittent and variable response to GH treatment due to noncompliance; recent recorded height was ˗3.6SD at 13.9 and he was early pubertal. Father had a history of childhood growth hormone treatment and is 151 cm tall, 2 paternal aunts did not receive treatment and are 145 cm tall, 3 children of these aunts are diagnosed with GHD. There is no maternal family history of GHD; mother is 155 cm. Proband testing revealed heterozygous GH1 c.291 + 34G>C (EGL Genetics), classified as a variant of unknown significance; father was also found to have this variant, mother was negative. Genetic testing for of additional family members is under consideration. Conclusion: Nine of 96 heterozygous GH1 variants are located in intron 3. Two have been classified as pathogenic and are predicted to cause exon skipping. Our proband’s variant cannot be considered a canonical splice site or in a mutational hot spot but has extremely low frequency in population databases. Functional studies clan clarify if our proband’s variant results in a 17.5 kDa GH isoform and dominant negative effect on full length GH production with potential detrimental effects on other anterior pituitary hormones. We present the second GHD pedigree with GH1 c.291 + 34G>C mutation. As in the previous report (1), no other hormone deficiencies are identified, despite the appearance of an empty sella for our proband. Reference: (1) Cho SY, Ki, CS, Park, HD, et al. Genetic investigation of patients with undetectable peaks of growth hormone after two provocation tests. Clin Endocrinol 2013; 78: 317-20.

Comparison of Hematopoietic Stem Cell Transplantation Results in Patients with β-Thalassemia Major from Three Different Graft Types

Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative therapy for β-thalassemias that induces severe life-threatening complications. The human leukocyte antigen (HLA) registries and umbilical cord blood banks have carried out diligent searches to find matched unrelated donors (MUDs) for about 70.0% of patients from 2000 onwards. The chance of finding a non-sibling fully matched family donors is higher in some ethnic groups in which consanguineous marriages are common. We have studied and compared transplant complications and outcomes in different graft types (sibling, non-sibling family and unrelated). The non-sibling matched family donor (MFD) group consisted of four mothers, three fathers, five cousins, one paternal uncle and one paternal aunt. There was no significant difference in the mean transfused CD34+ cells, engraftment, median days of neutrophil and platelet recovery were achieved (p > 0.05). The distribution of postttransplant complication did not show any significant difference between groups (p > 0.05). In univariate analysis and multivarite analyses, age, gender, Pesaro risk group (I-II vs. III) and ABO incompatibilty demonstrated a significant difference in disease free survival (p < 0.05). Furthermore, in the second step of investigating overall survival (OS), age, gender and Pesaro risk group (I-II vs. III) showed a significant difference (p < 0.05). There was no significant difference in transplant-related mortality (TRM) between groups. Non-sibling related donor transplants are important for populations where consanguineous marriages are common. Transplant groups according to graft type had similar thalassemia-free survival (TFS) and OS when using a treosulfan-based regimen in our study.

Abstract 13743: A Tale of Syncope, Prolonged QT and ICD

Introduction: Long QT syndrome (LQTS) was first described in the 1960s. It manifests clinically as syncope, cardiac arrest or sudden cardiac death. LQTS can be caused by 15 different genes. These mutations lead to action potential prolongation by causing impaired repolarizing currents. Case Discussion: A 29-year-old previously healthy Caucasian woman was admitted after recurrent episodes of syncope that happened within 1-month prior to the presentation. She was hemodynamically stable with normal vitals. Her ECG showed normal sinus rhythm with corrected QT (QTc) of 598ms. In the ED, she suffered an episode of sustained monomorphic ventricular tachycardia (VT) and underwent cardioversion. She was started on amiodarone infusion. Serial ECGs showed prolonged QTc. She had another episode of pulseless VT that terminated without defibrillation. She was transferred to our facility for further care. Her family history was significant for paternal aunt who had died unexpectedly at the age of 39. All her lab work including electrolytes, thyroid panel, cardiac enzymes, inflammatory markers and extended drug screen was unrevealing. Transthoracic echocardiogram showed normal biventricular size and function. Decision making: She was started on propranolol for possible LQTS. Cardiac MR did not show any evidence of structural abnormalities. Genetic panel was sent. Since myocarditis or familial LQTS could not be ruled out, we proceeded with implantable cardioverter defibrillator (ICD) implantation for secondary prevention. She was discharged home on nadolol. Conclusion: In the absence of genetic information, LQTS can be diagnosed in symptomatic patients with QTc &gt;480msec on serial ECGs after excluding secondary causes. Schwartz score comprising of ECG findings, symptoms, clinical &amp; family history is diagnostic when greater than 3.5. Beta-blockers are indicated in all patients with a clinical diagnosis. Patients must avoid any QT prolonging agents and strenuous exercise. An ICD is indicated in patients who suffered cardiac arrest. ICD may also be considered for primary prevention in high risk patients.

The Brokpa lexicon: Notes on selected semantic fields

A selection of semantic fields of the Brokpa lexicon are examined in some detail, focusing on both cross-linguistically salient as well as locally distinct concepts. Kinship terminology reflects traditional marriage customs through conflating in-laws with paternal aunts, maternal uncles and male cross-cousins. Different kinds of livestock such as yaks and cows are crossbred, giving rise to a wide variety of distinctly named hybrid offspring. Domestic animals receive characteristic onomatopoeic renderings of their vocalizations, and specialized summoning calls. A number of body parts are lexically not differentiated, such as hand and arm, foot and leg, finger and toe, while others like hair distinguish numerous types. Honorifics are found for body parts and kinship terms, among others. Finally, numerals mix a decimal with a more archaic vigesimal system.

“My Rapidly Growing Neck”

“My Rapidly Growing Neck”

Desmoid Type Fibromatosis of the Breast Masquerading as Breast Carcinoma: Value of Dynamic Magnetic Resonance Imaging and its Correlation

Desmoid type fibromatosis of the breast is a rare stromal tumor that accounts for <0.2% of all breast tumors. Bilateral and multicentric lesions are extremely rare, with only less than ten cases reported in the literature. Although benign, it is locally aggressive with frequent recurrence in up to almost one-third of the cases. We experienced our first case of bilateral multicentric breast fibromatosis in a 19-year-old woman, with a paternal aunt diagnosed with breast cancer at age 30, who presented to our institution with the chief complaint of retracted nipples for 1 year. The patient denied any history of trauma to her chest. Sonography showed suspicious bilateral hypoechoic masses. Magnetic resonance imaging (MRI) was performed for further evaluation because of the extensive involvement of both the breasts. This report aimed to illustrate the main clinical, radiological, and histopathological characteristics of this rare disease to increase awareness of this entity and discuss the role of MRI.

The Case | A hidden deposit

A 34-year-old white male presented with nephrotic syndrome. He had a past medical history of chronic schizophrenia well controlled on clozapine. There was no history of recent illness, travel, rash, or arthralgia. His family history was significant for lymphoma in his father and a paternal aunt with kidney disease of unknown etiology.

George F. Handel’s “How Beautiful Are the Feet” as Transformational Object: An Autobiographical Account

Using Christopher Bollas’s concept of transformational object, the author reflects on George F. Handel’s “How Beautiful Are the Feet” as a song that has sustained him and informed his vocational self-understanding as a pastoral theologian. The author reflects on the role of his mother and paternal aunts in fostering a model of care that instilled in him a sense of hope. The author concludes by reflecting on the kinetic quality of pastoral theology and the need to reclaim an agile, even playful understanding of hope.

Offspring Production Among the Relatives of Istmo Zapotec Men and Muxes.

Male androphilia (i.e., sexual attraction toward adult males) is influenced by biological factors, reliably occurs across diverse cultures, and has persisted over evolutionary time despite the fact that it reduces reproduction. One possible solution to this evolutionary paradox is the sexually antagonistic gene hypothesis (SAGH), which states that genes associated with male androphilia reduce reproduction when present in males but increase reproduction when present in their female relatives. The present study tested the SAGH among the Istmo Zapotec-a non-Euro-American culture in Oaxaca, Mexico, where transgender and cisgender androphilic males are known as muxe gunaa and muxe nguiiu, respectively. To test the SAGH, we compared offspring production by the biological relatives of muxe gunaa (n = 115), muxe nguiiu (n = 112), and gynephilic men (i.e., cisgender males who are sexually attracted to adult females; n = 171). The mothers and paternal aunts of muxe gunaa had higher offspring production than those of muxe nguiiu. Additionally, the relatives of muxe gunaa had more offspring than those of gynephilic men, whereas no such differences were found between the families of gynephilic men and muxe nguiiu. Elevated reproduction by the mothers and, particularly the aunts, of muxe gunaa is consistent with the SAGH. However, the absence of group differences between gynephilic men and muxe nguiiu, and the group differences between the two types of muxes are not predicted by the SAGH. This is the first study to demonstrate reproductive differences between kin of transgender and cisgender androphilic males within the same non-Euro-American culture.

Susan: A Partial Dictionary

This essay, written as a series of dictionary definitions, creates an incomplete assemblage of what the author knows of the life of her paternal aunt, Susan, who spent her adulthood institutionalized with schizophrenia. The essay explores the nature of experienced reality, subjectivity versus objectivity, gender expectations, and storytelling.

The heterozygous EDNRB mutation in a Chinese family with Waardenburg syndrome type I.

The genovariation of endothelin receptor type B (EDNRB) was identified in a Chinese family with Waardenburg syndrome type I (WS1) in the present study. WS1 was diagnosed in a 19-year-old young man, his older sister and aunt according to WS consortium criteria. After extracting genomic DNA from the peripheral blood samples, the coding exons and intronic regions of EDNRB were sequenced. A missense heterozygous mutation was found in the coding region of exon 2 in the EDNRB gene on chormosome 13q22.3 of the proband. The same mutation was detected in the proband's afflicted paternal aunt and first older sister. Subsequent polyphen analysis and three-dimensional modeling confirmed that the c.469A>G heterozygous mutation in EDNRB was possibly pathogenic. This is the first report of EDNRB mutation as a potential disease-causing mutation in Chinese patients with WS1.

Familial Platelet Disorder/Predisposition to Acute Myeloid Leukemia With Germline RUNX1 Mutation Masquerading as Idiopathic Thrombocytopenic Purpura: Case Study

Abstract A 25-year-old female underwent emergent laparoscopic salpingectomy when she presented with an ectopic pregnancy (G1P0). A bone marrow biopsy performed for moderate persistent thrombocytopenia (60-105 K/μL) showed normocellularity, maturing trilineage hematopoiesis, and mildly increased morphologically normal megakaryocytes reported as consistent with idiopathic thrombocytopenic purpura (ITP). However, on further inquiry, the patient stated that her sister, father, paternal aunt, and paternal grandfather have/had low platelets. Her father had been diagnosed with myelodysplasia (MDS). Her paternal grandmother had died of acute myeloid leukemia (AML). Thus, although her marrow morphology revealed no evidence of overt dysplasia and despite her normal karyotypic study, a sample was sent for RUNX1 sequence analysis. A splice site mutation (c.967 + 2_967 + 5delTAAG) in RUNX1 was detected and initially interpreted as a somatic mutation. However, given the strong family history of thrombocytopenia and MDS/AML, a sample from her father was also sent for RUNX1 sequence analysis, and the identical intronic sequence variant in the RUNX1 gene was detected in him. This confirmed the RUNX1 mutation to be germline. In the context of autosomal dominant thrombocytopenia in the patient’s family, the finding of this variant in the affected patient and her similarly affected father was consistent with a pathogenic role. Since this patient was of reproductive age actively trying to have children, these molecular genetic findings had important implications. She elected to undergo in vitro fertilization in order to choose embryos without the RUNX1 mutation for implantation. Considering that her father and paternal grandmother developed MDS/AML, and because familial platelet disorder with predisposition to AML appears to show “anticipation,” she would require close future monitoring for blastic transformation. This case illustrates the significance of careful history taking and high suspicion index that can lead to simplified targeted cost-effective molecular testing resulting in the correct diagnosis without necessarily employing large gene panels.

Psychiatrie et violences intrafamiliales. Quand dire c’est aliéner

ObjectiveThis article examines the effects of the forced marriage injunction on ten girls. Paternal aunts ordered them to stop theirs studies and marry men chosen by their families. This extreme severity provokes hostile conflict, school demotivation, and fear to be subjected to the husband's arbitrariness. The article presents clinical data collecting and analyzing method, effects of this injunction and three profiles of emancipation. MethodThe participants of the study are 16 to 18 year's old immigrant's girls who are recruited through an intercultural association where the author has a research contract on domestic violence. They come from African families where parental and social authority is carried by the father, mother and paternal aunt. Migratory process, as well as plural, complex even divergent cultural legacies exposes them to cumulative traumas. The injunction of forced marriage exasperates their vulnerability, weakens their psychological resources and hinders on their efforts to work through the pathogenic traces of these legacies. The author conducted four research interviews aimed at renewing the state of knowledge about adolescent processes facing the forced marriage injunction. The first two interviews aimed to create a bond of trust with the girls and clarify their problem, the third to assess their degree of vulnerability. The last aimed to study the links of descent, generational transmission and conflicts of loyalty. The analysis evaluates the quality of biopsychosocial maturation. ResultsEffects – The aunt's injunctive speech denies the verifiable and evaluative dimension of language risks. It makes an alienating interpretation of female destiny. The adolescents live it like a cruelty that condemns them to become slaves in the social and conjugal bond. It has visibly alienated psychic conflicts into pathogenic ones, created hatred and mutual rejection. It has also created confusion in the language between aunts and nieces. The aunts are trapped in a compulsion of repetition of an obsolete custom and seem blind to their niece's request for initiation into becoming responsible and autonomous. This request has turned into a nightmare that engulfs them with anguish and fantasies of being banished, killed or sacrificed as a “fresh flesh” to the husband's arbitrary speech and behavior. Three emancipation profilesFor two girls, oscillation between hope and intense depression related to multiple crisis of mental maturation has turned into depression diagnosed by a psychiatrist. But the psychiatric care, followed by psychological and social one allowed them to find a psychic balance and to resume their studies. Three girls made a positive cultural transgression. Breaking taboos and loyalty conflicts, they summoned their parents before a public authority, provoked an intercultural conflict mediated by the law and justice. They understood that the custom transgressed the rules of the palaver, discussion of a family drama or social in a space protecting the protagonists against the arbitrary of the language and the behaviors. Their transgression is thus a counter-transgression that demands to play reasonably with words, scenes and conduct to create the meaning of living together. Five girls, who conceived their problem as generational, asked for community mediation. They realized that their aunts and grandmothers cannot help them emancipate themselves because they all are caught in a compulsion to repeat an androcentric social model and its discourse that only value them as producers of boys, future soldiers, fathers or lineage continuators. This model has become unsuitable. Girls solicit grandfathers and religious leaders who are aware of this obsolescence and who are empowered by their authority and place to bring about cultural change in the community. ConclusionLanguage, the fundamental tool for the psychic maturation of individuals and societies, can create a pathogenic emancipation conflict between adults and adolescents and lead to devastating arbitrariness. In this context, some adolescents go through a positive cultural transgression to access the maturation of their psychic processes.

Genomic Profiling of Vulvar Lichen Sclerosus Patients Shows Possible Pathogenetic Disease Mechanisms.

Vulvar lichen sclerosus (LS) is known to occur in families, suggesting a genetic link. Genomic profiling of patients with vulvar LS was investigated to find underlying pathogenetic mechanisms, with the hope that targeted therapies and future clinical research will arise. Two unrelated families with vulvar LS were investigated using whole-exome sequencing. Five affected sisters from 1 family were compared with their unaffected paternal aunt (unaffected control). A mother-daughter pair from a second affected family was compared with the first family. The results of the sequencing were compared with population-specific allele frequency databases to prioritize potential variants contributing to vulvar LS development. Recurrent germ-line variants in 4 genes were identified as likely to be deleterious to proper protein function in all of the 7 affected patients, but not in the unaffected control. The genes with variants included CD177 (neutrophil activation), CD200 (inhibitory signal to macrophages), ANKRD18A (ankyrin repeat protein, epigenetic regulation), and LATS2 (co-repressor of androgen signaling). Although many providers may see a mother and daughter with vulvar LS, this condition is rarely seen in multiple family members who are available for genetic testing. This is the first report to detail genomic profiling related to a familial association of vulvar LS.

New Light on Early Middle English Borrowing from Anglo-Norman: Investigating Kinship Terms in grand‑

Abstract It is well known that the set of kinship terms in Middle English showed considerable influence from French. In the case of aunt and uncle, this accompanied major restructuring of the system of kinship terms, as the Old English set of four distinct terms for paternal and maternal uncles and aunts were replaced by just two terms for ‘uncle’ and ‘aunt’, regardless of whether paternal or maternal. In comparison, the words for ‘grandfather’ and ‘grandmother’ have attracted little attention, as their story has appeared simpler: Old English had words for ‘grandfather’ and ‘grandmother’, irrespective of whether paternal or maternal, and so did Middle English. The terms are also similar in structure, with native terms in which words for ‘father’ or ‘mother’ are the head and eald ‘old’ is the modifier (whether in a compound or a phrasal structure) being replaced by borrowed terms (grandsire, granddame) or hybrid terms (grandfather, grandmother) in which French grand ‘big’ is the modifier. This paper shows that behind this apparently simple story there lurk some significant complications which point to considerable disruption and instability in the terms for ‘grandfather’ and ‘grandmother’ in both Middle English and French (with interesting and perhaps significant parallels also in other West Germanic languages). Consideration of these complications also casts new light on early lexical borrowing into Middle English from Anglo-Norman.

SUN-205 A Case of 46XY Mixed Gonadal Dysgenesis Presenting with Unilateral Gonad and Hemiuterus: Family History Dictates Sex Assignment

Background: Disorders of sex differentiation (DSDs) result from an atypical congenital development of chromosomal, gonadal, or anatomical sex. Mixed gonadal dysgenesis, a rare DSD, is the presence of both ovarian and testicular tissue. Early sex assignment is challenging due to the variable clinical, cytogenetic, and histopathological presentations. Clinical Case: A 1-day-old born from an uncomplicated pregnancy at 36+4/7 weeks gestation (birth weight 3.7 kg) was noted to have ambiguous genitalia. Upon examination, external genitalia was a bifid scrotum with palpable right scrotal and non-palpable left gonad; no hyperpigmentation. Phallus length was 2.5 cm and width was 1.3 cm with chordee (Prader Stage 3 hypospadias) and a single proximal urogenital sinus (anogenital ratio 1.3). Family history included a paternal uncle and two paternal cousins with ambiguous genitalia requiring surgy. The paternal uncle had two healthy daughters without fertility interventions. Also, three paternal aunts are significantly taller and infertile. Father has gynecomastia. No consanguinity. The initial investigation found normal electrolytes, LH 2.1 mIU/ml, and FSH 3.1 mIU/ml. Anti-Mullerian hormone (AMH, 20.47 ng/mL) and testosterone levels (42.6 ng/dL) were low for a male. High-resolution karyotype showed 46, XY with no mosaicism and a positive FISH SRY. Chromosomal microarray analysis was unremarkable for small deletions or duplications. A high-dose (150 mcg) ACTH stimulation test ruled out adrenal steroid biosynthesis defects. Renin and aldosterone were unremarkable. An hCG stimulation test showed appropriate rise in testosterone (443.1 ng/dL), androstenedione (112 ng/dL), and 5-alpha-dihydrotestosterone (1027.2 pg/mL). Ultrasound showed a single right testicle (~3 mL volume) within the hemiscrotum, a left inguinal hernia containing mesentery, and a left hemiuterus with no ovaries. A genitogram showed a urogenital sinus with a normal-appearing vaginal canal and elongated female urethra. No vesicoureteral reflux or other perineal orifices. The low AMH with an appropriate rise in testosterone following hCG stimulation and the presence of male and female reproductive organs in an undervirulized XY suggests mixed gonadal dysgenesis. Sex assignment was deferred by the medical team until further evaluation, but the parents chose to raise as a male based on their family history. Extended family studies are in process. Conclusion: The wide clinical and molecular variation in mixed gonadal dysgenesis constitutes a challenge for sex assignment. A multi-disciplinary team approach before sex assignment is crucial, including accurate assessment of external and internal genitalia, biochemical gonadal function, and cytogenetic testing. Among the multiple genetic variants known to cause mixed gonadal dysgenesis, highest on our differential is DMRT1.

SAT-595 Ventricular Fibrillation as a Manifestation of Hyperthyroidism

Background: Thyrotoxicosis is a known cause of atrial arrhythmias however, ventricular arrhythmias in this setting are rare. We report a case of ventricular fibrillation (VF) in a patient with Graves hyperthyroidism in the absence of coronary disease. Clinical Case: A 55-year old woman with hypertension and a self-reported thyroid nodule presented with a two week history of general malaise, palpations, diarrhea and muscle aches. Her mother had a goiter and paternal aunt required a thyroidectomy. Both her father and paternal uncle died at age 58 and 60 respectively of myocardial infarction. She was tachycardic to 125 beats per minute (bpm) and had a firm goiter with no bruit and normal reflexes. TSH was <0.01, free T4 > 6.99 ng/dL (n= 0.7-2.19 ng/dL), total T3 > 7.81 ng/mL (n=0.97 -1.7 ng/mL), thyroid stimulating immunoglobulin 516 % (n= <140%), and thyroid binding inhibitory immunoglobulin was 82.5% (n=<16%). Treatment with dexamethasone, methimazole, and propranolol was initiated. Homogenous increased uptake was seen in the thyroid gland on nuclear medicine scan. On day two of admission, her total T3 remained > 7.81 ng/mL despite therapy but her heart rate was better controlled at 100 bpm. However, that night she suffered a 40- minute cardiac arrest from VF. Spontaneous circulation was restored after multiple shocks, amiodarone and lidocaine, and then temporary pacing for bradycardia. She received a total of 440mg of propranolol and 40mg of methimazole prior to cardiac arrest. Serum potassium was normal pre arrest but rose to 6.9 mmol/L (n=3.5-5.1 mmol/L) after. Given the bradycardia, glucagon was given for possible beta blocker toxicity although this was thought to be unlikely as telemetry did not reveal pre-arrest bradycardia. There was no evidence of a coronary event since admission troponin was negative and post arrest troponin was only mild elevated with a flat trend. No wall motion abnormality was see on echocardiogram and ventricular function was preserved. Cardiac catheterization was deferred due to declining renal function. Subsequent myocardial perfusion imaging displayed only an apical cap artifact and coronary CT angiogram was free from atherosclerosis. She had no further arrhythmias. An implantable cardioverter defibrillator was placed prior to discharge for secondary prevention of ventricular arrhythmias. Conclusion: VF in the absence of underlying coronary disease or heart failure is rare in thyrotoxicosis. Thyroid hormone induced coronary vasospasm and activation of regionally varied beta-adrenergic receptors are proposed mechanisms for VF. Further, some individuals may have genetic predisposition to this in the setting of hyperthyroidism. This case highlights the urgency of achieving a euthyroid state and closely monitoring individuals with a family or personal history of ventricular arrhythmias or sudden cardiac death.

Family history of cancer and risk of paediatric and young adult\u2019s testicular cancer: A Norwegian cohort study

BackgroundThe aim of this study was to examine the association of a family history of cancer with the risk of testicular cancer in young adults.MethodsThis is a prospective cohort study including 1,974,287 males born 1951–2015, of whom 2686 were diagnosed with TC before the age of 30.ResultsA history of TC in male relatives was significantly associated with a diagnosis of TC among children and young adults, including brothers (6.3-fold), sons (4.7-fold), fathers (4.4-fold), paternal uncles (2.0-fold) and maternal uncles (1.9-fold). Individuals with a father diagnosed with a carcinoma or sarcoma showed an elevated risk (1.1-fold and 1.8-fold, respectively). A family history of mesothelioma was positively associated with a risk of TC [(father (2.8-fold), mother (4.6-fold) and maternal uncles and aunt (4.4-fold)]. Elevated risks were also observed when siblings were diagnosed with malignant melanoma (1.4-fold). The risk of TC was also increased when fathers (11.1-fold), paternal (4.9-fold) and maternal uncles and aunts (4.6-fold) were diagnosed with malignant neuroepithelial-tumours.ConclusionWe found an increased risk of TC among children and young adults with a family history of TC, carcinoma, mesothelioma, sarcoma, malignant melanoma and malignant neuroepithelial tumours. Hereditary cancer syndromes might underlie some of the associations reported in this study.

Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension.

Although mutations in several genes have been reported in pulmonary arterial hypertension (PAH), most of PAH cases do not carry these mutations. This study aimed to identify a novel cause of PAH. To determine the disease-causing variants, direct sequencing and multiplex ligation-dependent probe amplification were performed to analyze 18 families with multiple affected family members with PAH. In one of the 18 families with PAH, no disease-causing variants were found in any of BMPR2, ACVRL1, ENG, SMAD1/4/8, BMPR1B, NOTCH3, CAV1, or KCNK3. In this family, a female proband and her paternal aunt developed PAH in their childhood. Whole-exome next-generation sequencing was performed in the 2 PAH patients and the proband’s healthy mother, and a BRCA1-associated protein (BRAP) gene variant, p.Arg554Leu, was identified in the 2 family members with PAH, but not in the proband’s mother without PAH. Functional analyses were performed using human pulmonary arterial smooth muscle cells (hPASMCs). Knockdown of BRAP via small interfering RNA in hPASMCs induced p53 signaling pathway activation and decreased cell proliferation. Overexpression of either wild-type BRAP or p.Arg554Leu-BRAP cDNA constructs caused cell death confounding these studies, however we observed higher levels of p53 signaling inactivation and hPASMC proliferation in cells expressing p.Arg554Leu-BRAP compared to wild-type BRAP. In addition, p.Arg554Leu-BRAP induced decreased apoptosis of hPASMCs compared with wild-type BRAP. In conclusion, we have identified a novel variant of BRAP in a Japanese family with PAH and our results suggest it could have a gain-of-function. This study sheds light on new mechanism of PAH pathogenesis.

Inherited Cryptic Translocation t(12;17)(q24.3;p13.3) Causing Recurrence of Miller-Dieker Syndrome

The Miller-Dieker syndrome (MDS) is a severe neurological disorder characterized by lissencephaly, facial dysmorphies, global developmental delay and severe seizures. A deletion at 17p13.3, including the lissencephaly gene (LIS1), is usually present as part of a contiguous gene syndrome. Around 20% of case LSI1 gene is resulting from inherited balanced translocation. We present the case of a family with cryptic t(12;17) translocation identified by FISH in two generations. The proband had clinical features of MDS. The parents reported a paternal aunt deceased as a young infant due to “uncontrolled seizures and severe developmental delay. The GTG analysis of proband suggested deletion at 17p13.3 that was confirmed by FISH. The parental investigation by FISH revealed a paternal translocation involving regions 12qter and 17p13.3. This familial chromosomal rearrangement associated to MDS has modified the genetic counseling of the couple. From a very low risk of recurrence on the cases associated to a <i>de novo</i> del17p13.3, to a much higher risk, since it was associated to a familial translocation. This risk of recurrence, considering meiotic segregation of balanced translocation involving the 17p13.3 region is relatively high (12%) which alone would justify prenatal diagnosis. Classical and molecular cytogenetic investigations in the fetal sample were normal reassuring the couple as to a normal baby with neither 17p13.3 deletion nor carrier of the paternal translocation. This rare case identified by FISH demonstrate the need of providing molecular cytogenetic analysis for other family members; since, criptical balanced rearrangements may segregate undetected. This case evidences the importance of molecular study of parents of children with microdeletions, which could considerably improve the certainties regarding genetic counseling.