Hereditary fragility of bone (fragilitas osseus, osteopsathyrosis)

Mode of access: Internet.

A new type of hereditary brachyphalangy in man,

"List of literature": p. 63-64.

Hereditary pancreatitis in a family of Aboriginal descent

Hereditary pancreatitis is an autosomal dominant condition characterized by recurrent episodes of acute pancreatitis, usually starting in childhood. We present a family who was ascertained when an 11-year-old girl presented with an episode of acute pancreatitis. Her father and other family members had also had recurrent bouts of acute pancreatitis. Genetic testing revealed a pathogenic mutation in the cationic trypsinogen gene in the proband, her father and her paternal grandmother. As far as we are aware, this is the first Aboriginal kindred with mutation-proven hereditary pancreatitis. Hereditary pancreatitis is an important differential diagnosis to consider in a patient with recurrent episodes of acute pancreatitis with no obvious precipitating cause. This family is of Aboriginal descent and the implications of the family's background are also discussed when considering the aetiology of the condition. We emphasize the need to ascertain a full family history from patients with a history of repeated episodes of acute pancreatitis and also emphasize the need to avoid ethnic stereotypes when assessing patients.

Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis

HFE-associated hereditary haemochromatosis is a recessive, iron-overload disorder that affects about one in 200 north Europeans and that can be easily prevented. However, genetic screening for this disease is controversial, and so we assessed whether such screening was suitable for communities. Cheek-brush screening for the Cys282Tyr HFE mutation was offered to individuals in the workplace. Outcomes were assessed by questionnaires before and after testing. 11307 individuals were screened. We recorded no increase in anxiety. in individuals who were homozygous for the Cys282Tyr mutation or non-homozygous. Self-reported tiredness before testing was significantly higher in homozygous participants than in non-homozygous participants (chi(2) test, p=0.029). Of the 47 homozygous individuals identified, 46 have taken steps to treat or prevent iron accumulation. Population genetic screening for HFE-associated hereditary haemochromatosis can be practicable and acceptable.

Initiation and progression of ossification of the posterior longitudinal ligament of the cervical spine in the hereditary spinal hyperostotic mouse (twy/twy)

Ossification of the posterior longitudinal ligament (OPLL) is a significantly critical pathology that can eventually cause serious myelopathy. Ossification commences in the vertebral posterior longitudinal ligaments, and intensifies and spreads with the progression of the disease, resulting in osseous projections and compression of the spinal cord. However, the paucity of histological studies the underlying mechanisms of calcification and ossification processes remain obscure. The pathological process could be simulated in the ossifying process of the ligament in mutant spinal hyperostotic mouse (twy/twy). The aim of this study is to observe that enlargement of the nucleus pulposus followed by herniation, disruption and regenerative proliferation of annulus fibrosus cartilaginous tissues participated in the initiation of ossification of the posterior longitudinal ligament of twy/twy mice.

A Québec mystery unveiled : the quest to understand hereditary sensory and autonomic neuropathy type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

A Québec mystery unveiled : the quest to understand hereditary sensory and autonomic neuropathy type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Fresh Frozen Plasma in Hereditary Angioedema Crisis: To Give or Not To Give?

Objectives: Fresh frozen plasma (FFP) has been used in angioedema crises, however there is a risk of aggravating the symptoms as well as transmitting infections. In this report, the authors emphasize the dangers of this therapy. Materials and methods: A 25-year-old woman with hereditary angioedema (HAE) was treated with FFP after which her symptoms escalated. Results: Administration of purified C1-inhibitor (C1-INH) resulted in relief of her symptoms. Conclusions: FFP is to be avoided in a HAE crisis. Newer therapies for angioedema are preferred.

Do hereditary syndrome-related gynecologic cancers have any specific features?

Hereditary syndromes are responsible for 10 % of gynaecologic cancers, among which hereditary breastovarian cancer and hereditary non-polyposis colon cancer syndromes, known as HBOC and Lynch syndromes respectively, present the highest relative risk. The latter predisposes to endometrial cancer and both contribute to ovarian cancer. Cowden syndrome-related endometrial cancer and the increased risk of ovarian, uterine and cervical cancers associated with Peutz-Jeghers syndrome, are also demonstrated, while Li-Fraumeni syndrome patients are prone to develop ovarian and endometrial cancers. Despite these syndromes’ susceptibility to gynaecologic cancers being consensual, it is still not clear whether these tumours have any epidemiologic, clinical, pathologic or imaging specific features that could allow any of the intervening physicians to raise suspicion of a hereditary syndrome in patients without known genetic risk. Moreover, controversy exists regarding both screening and surveillance schemes. Our literature review provides an updated perspective on the evidence-based specific features of tumours related to each of these syndromes as well as on the most accepted screening and surveillance guidelines. In addition, some illustrative cases are presented.

Aluminum and iron can be deposited in the calcified matrix of bone exostoses.

International audience

Experience of a Single Center in NTBC Use in Management of Hereditary Tyrosinemia Type I in Libya

Background: Hereditary Tyrosinemia type I (HTI) is a metabolic disease caused by deficiency of fumarylacetoacetate hydrolase enzyme. Objectives: This study reports beside its clinical and biochemical presentation, the outcome of NTBC [2- (2-nitro-4-trifloro-methylbenzoyl)-1, 3-cyclohexanedion] treatment of the disease and evaluates its biochemical markers in 16 pediatric Libyan patients. Patients and Methods: The diagnosis was based on presence of high tyrosine levels in blood and succinylacetone in urine. Results: The consanguinity rate was 81.2%, the median age at onset, at diagnosis and at starting treatment were 4.5, 8, and 9.5 months respectively. At presentation hepatomegaly, jaundice, rickets and high gamma glutamyl transferase (GGT) were observed in 87.5% of patients. All patients had extremely high alpha fetoprotein (AFP) and high alkaline phosphatase (ALP) levels. Fifteen patients were treated with NTBC, normalization of PT (Prothrombine time) was achieved in average in 14 days. The other biochemical parameters of liver function (transaminases, GGT, ALP, bilirubin and albumin) took longer to improve and several months to be normalized. Survival rate with NTBC was 86.6%. Patients who started treatment in a median of 3 months post onset observed a fast drop of AFP in 90.6% of patients (P = 0.003). Abnormal liver function and rickets were the common presentations, GGT was an early cholestatic sensitive test. ALP was constantly high even in asymptomatic patients. Conclusions: In HT1 a faster dropping of AFP is a marker of good prognosis.

Whole Exome Sequencing widens the genetic landscape of Hereditary Optic Neuropathies

Hereditary optic neuropathies (HON) are a genetic cause of visual impairment characterized by degeneration of retinal ganglion cells. The majority of HON are caused by pathogenic variants in mtDNA genes and in gene OPA1. However, several other genes can cause optic atrophy and can only be identified by high throughput genetic analysis. Whole Exome Sequencing (WES) is becoming the primary choice in rare disease molecular diagnosis, being both cost effective and informative. We performed WES on a cohort of 106 cases, of which 74 isolated ON patients (ON) and 32 syndromic ON patients (sON). The total diagnostic yield amounts to 27%, slightly higher for syndromic ON (31%) than for isolated ON (26%). The majority of genes found are related to mitochondrial function and already reported for harbouring HON pathogenic variants: ACO2, AFG3L2, C19orf12, DNAJC30, FDXR, MECR, MTFMT, NDUFAF2, NDUFB11, NDUFV2, OPA1, PDSS1, SDHA, SSBP1, and WFS1. Among these OPA1, ACO2, and WFS1 were confirmed as the most relevant genetic causes of ON. Moreover, several genes were identified, especially in sON patients, with direct impairment of non-mitochondrial molecular pathways: from autophagy and ubiquitin system (LYST, SNF8, WDR45, UCHL1), to neural cells development and function (KIF1A, GFAP, EPHB2, CACNA1A, CACNA1F), but also vitamin metabolism (SLC52A2, BTD), cilia structure (USH2A), and nuclear pore shuttling (NUTF2). Functional validation on yeast model was performed for pathogenic variants detected in MECR, MTFMT, SDHA, and UCHL1 genes. For SDHA and UCHL1 also muscle biopsy and fibroblast cell lines from patients were analysed, pointing to possible pathogenic mechanisms that will be investigated in further studies. In conclusion, WES proved to be an efficient tool when applied to our ON cohort, for both common disease-genes identification and novel genes discovery. It is therefore recommended to consider WES in ON molecular diagnostic pipeline, as for other rare genetic diseases.

Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral center

- Aims: Hereditary Transthyretin Amyloidosis (ATTRv) is one of the leading etiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow up. - Methods: Observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral center in Bologna, Italy, between 1984 and 2022. - Results: Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype and 121 mixed phenotype. Twenty-three different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months data from 290 subjects were analyzed; among them 111 (38.3%) died and 123 (42.4%) had a major clinical event (death or hospitalization for heart failure). Nine (11.5%) of the 78 asymptomatic carriers showed signs and symptoms of the disease. Carriers had a prognosis comparable to healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, NYHA functional class, left ventricular ejection fraction, mPND score and disease-modifying therapy were independently associated with survival. - Conclusions: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral center in Italy. Three main phenotypes can be identified (cardiac, neurological and mixed) with specific clinical and instrumental features. Family screening programs are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality.