Clinical and functional characterization of germline PIK3CA variants in patients with PIK3CA-related overgrowth spectrum disorders.

Mosaic variants in the PIK3CA gene, encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), produce constitutive PI3K activation, which causes PIK3CA-related overgrowth spectrum disorders. To date, fewer than 20 patients have been described with germline alterations in PIK3CA. In this study, we describe three unrelated individuals with overgrowth and germline PIK3CA variants. These variants were discovered through whole-exome sequencing and confirmed as germline by testing multiple tissue types, when available. Functional analysis using Patient 1's fibroblast cell line and two previously reported patients' cell lines showed increased phosphorylation of AKT during cellular starvation revealing constitutive activation of the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway. Alternatively, stimulation of the cells by fetal bovine serum produced a reduced response, indicating an activated status of the PI3K complex reducing the pathway response to further external stimulation. Additional studies utilizing Biolog Phenotype Microarray technology indicated reduced energy production when cells were exposed to growth factors stimulating the PI3K/AKT/mTOR pathway, confirming the trend observed in the AKT phosphorylation test after stimulation. Furthermore, treatment with inhibitors of the PI3K/AKT/mTOR pathway rescued the normal energy response in the patients' cells. Collectively, these data demonstrate that disease-causing germline PIK3CA variants have a functional consequence, similar to mosaic variants in the PI3K/AKT/mTOR pathway.

Congenital hepatic fibrosis: case report and review of literature.

Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation; it often coexists with Caroli's disease, von Meyenburg complexes, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). Although CHF was first named and described in detail by Kerr et al. in 1961. Its pathogenesis still remains unclear. The exact incidence and prevalence are not known, and only a few hundred patients with CHF have been reported in the literature to date. However, with the development of noninvasive diagnostic techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), CHF may now be more frequently detected. Anatomopathological examination of liver biopsy is the gold standard in diagnosis of CHF. Patients with CHF exhibit variable clinical presentations, ranging from no symptoms to severe symptoms such as acute hepatic decompensation and even cirrhosis. The most common presentations in these patients are splenomegaly, esophageal varices, and gastrointestinal bleeding due to portal hypertension. In addition, in younger children, CHF often is accompanied by renal cysts or increased renal echogenicity. Great variability exists among the signs and symptoms of the disease from early childhood to the 5th or 6th decade of life, and in most patients the disorder is diagnosed during adolescence or young adulthood. Here, we present two cases of congenital hepatic fibrosis in 2-years-old girl and 12-year-old male who had been referred for evaluation of an abdominal distension with persistent hyper-transaminasemia and cholestasis, the diagnostic was made according to the results of medical imaging (CT or MRI), a liver biopsy, and genetic testing.

Ddhd1 knockout mouse as a model of locomotive and physiological abnormality in familial spastic paraplegia.

We have previously reported a novel homozygous 4-bp deletion in DDHD1 as the responsible variant for spastic paraplegia type 28 (SPG28; OMIM#609340). The variant causes a frameshift, resulting in a functionally null allele in the patient. DDHD1 encodes phospholipase A1 (PLA1) catalyzing phosphatidylinositol to lysophosphatidylinositol (LPI). To clarify the pathogenic mechanism of SPG28, we established Ddhd1 knockout mice (Ddhd1[-/-]) carrying a 5-bp deletion in Ddhd1, resulting in a premature termination of translation at a position similar to that of the patient. We observed a significant decrease in foot-base angle (FBA) in aged Ddhd1(-/-) (24 months of age) and a significant decrease in LPI 20:4 (sn-2) in Ddhd1(-/-) cerebra (26 months of age). These changes in FBA were not observed in 14 months of age. We also observed significant changes of expression levels of 22 genes in the Ddhd1(-/-) cerebra (26 months of age). Gene Ontology (GO) terms relating to the nervous system and cell-cell communications were significantly enriched. We conclude that the reduced signaling of LPI 20:4 (sn-2) by PLA1 dysfunction is responsible for the locomotive abnormality in SPG28, further suggesting that the reduction of downstream signaling such as GPR55 which is agonized by LPI is involved in the pathogenesis of SPG28.

Titinopathy, an atypical respiratory failure.

Hereditary myopathy with early respiratory failure is a neuromuscular disease with an autosomal dominant inheritance pattern. Clinical presentation is characterised by proximal and distal muscle weakness, exertional dyspnoea and generalised fatigue. There is no disease-modifying therapy and the prognosis is unknown. Herein we present a case of a 40-year-old woman with long-standing asthenia and apathy and, more recently, daytime sleepiness, dyspnoea and difficulty in walking. A hypercapnic respiratory failure with severe acidemia was identified. The muscle biopsy showed the presence of cytoplasmatic bodies and rimmed vacuoles, suggestive of a hereditary myopathy with early respiratory failure disease. The genetic study confirmed this diagnosis identifying a heterozygous mutation on c.95134T>C (p.Cys31712Arg) in exon 343 in the titin gene. The patient was discharged home under supportive treatment with non-invasive ventilation.

Possible acquired gastrointestinal polyposis in a childhood cancer survivor.

Childhood cancer survivors (CCSs) are at an increased risk for secondary cancers, including colorectal, thyroid, lung, and breast. Treatment with abdominal radiotherapy and/or alkylating agent chemotherapy has been associated with an increased risk for colorectal adenomas and colorectal cancer (CRC) in CCSs. The phenotype of therapy-associated polyposis (TAP) is not well-understood, given the paucity of cases described in the literature. Further defining the phenotype of TAP is important to increase the primary care provider's awareness of when to begin CRC screening in these patients. We present a case of a patient with possible acquired polyposis that seems to meet the criteria identified in the literature for TAP. The purpose of this case study is to add to the body of knowledge related to TAP, further defining the phenotype. Better understanding of therapy-related risks in CCSs and hereditary predisposition will provide primary care providers and their patients with an improved plan for CRC screening.

Towards Central Nervous System Involvement in Adults with Hereditary Myopathies.

There is increasing evidence of central nervous system involvement in numerous neuromuscular disorders primarily considered diseases of skeletal muscle. Our knowledge on cerebral affection in myopathies is expanding continuously due to a better understanding of the genetic background and underlying pathophysiological mechanisms. Intriguingly, there is a remarkable overlap of brain pathology in muscular diseases with pathomechanisms involved in neurodegenerative or neurodevelopmental disorders. A rapid progress in advanced neuroimaging techniques results in further detailed insight into structural and functional cerebral abnormalities. The spectrum of clinical manifestations is broad and includes movement disorders, neurovascular complications, paroxysmal neurological symptoms like migraine and epileptic seizures, but also behavioural abnormalities and cognitive dysfunction. Cerebral involvement implies a high socio-economic and personal burden in adult patients sometimes exceeding the everyday challenges associated with muscle weakness. It is especially important to clarify the nature and natural history of brain affection against the background of upcoming specific treatment regimen in hereditary myopathies that should address the brain as a secondary target. This review aims to highlight the character and extent of central nervous system involvement in patients with hereditary myopathies manifesting in adulthood, however also includes some childhood-onset diseases with brain abnormalities that transfer into adult neurological care.

Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a B cell lymphoma characterized by few malignant cells and numerous immune effector cells in the tumour microenvironment. The incidence of HL is highest in adolescents and young adults, although HL can affect elderly individuals. Diagnosis is based on histological and immunohistochemical analyses of tissue from a lymph node biopsy; the tissue morphology and antigen expression profile enable classification into one of the four types of classic HL (nodular sclerosis, mixed cellularity, lymphocyte-depleted or lymphocyte-rich HL), which account for the majority of cases, or nodular lymphocyte-predominant HL. Although uncommon, HL remains a crucial test case for progress in cancer treatment. HL was among the first systemic neoplasms shown to be curable with radiation therapy and multiagent chemotherapy. The goal of multimodality therapy is to minimize lifelong residual treatment-associated toxicity while maintaining high levels of effectiveness. Recurrent or refractory disease can be effectively treated or cured with high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation, and prospective trials have demonstrated the potency of immunotherapeutic approaches with antibody-drug conjugates and immune checkpoint inhibitors. This Primer explores the wealth of information that has been assembled to understand HL; these updated observations verify that HL investigation and treatment remain at the leading edge of oncological research.

The Effect of Comorbidities on Wound Healing.

Wound healing is affected by several factors. Preexisting diagnoses may significantly alter, delay, or inhibit normal wound healing. This is most commonly seen with chronic disorders, such as diabetes and renal failure, but also occurs secondary to aging and substance abuse. Less commonly, genetic or inflammatory disorders are the cause of delayed wound healing. In some cases, it is not the illness, but the treatment that can inhibit wound healing. This is seen in patients getting chemotherapy, radiation, steroids, methotrexate, and a host of other medications. Understanding these processes may help treat or avoid wound healing problems.

Epilepsy and Electroencephalographic Abnormalities in SATB2-Associated Syndrome.

BACKGROUND: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. METHODS: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. RESULTS: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). CONCLUSIONS: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.

Pulmonary Alveolar Microlithiasis: a Case Report in King Hussein Medical Center (KHMC), Amman, Jordan.

INTRODUCTION: Pulmonary Alveolar Microlithiasis (PAM) is a rare disorder that can affect patients at any age, although it is more common to present in the third and fourth decades of life. Most patients are asymptomatic at the time of diagnosis. However, some may present with symptoms of dyspnea or cough. PAM can be sporadic, or it can be hereditary. AIM: To focus on the importance of using chest CT scans along with bone scintigraphy to aid in the diagnosis of PAM. The importance of screening all family members is also addressed. CASE REPORT: In our case, the patient was a 21-year-old male, coming for routine check-up to be recruited in the army. He was referred to our clinic after the examining doctor noticed that his chest X-Ray was not normal. Upon revising his chest X-ray, he was found to have bilateral fine reticular infiltrates. His physical examination was unremarkable. His spirometry and DLCO were normal. A high-resolution chest CT scan was done, and showed diffuse bilateral microcalcifications with bilateral interstitial and septal thickening. To confirm the diagnosis of PAM, a Technetium-99m methylene diphosphonate (Tc-99m MDP) whole body bone scintigraphy was done, and it showed diffusely increased radiotracer uptake in both lungs. His family members were screened for PAM. His father and sister, who were completely asymptomatic and with normal pulmonary function tests, were found to have PAM as well. CONCLUSION: The use of bone scintigraphy plays an integral role in diagnosing patients with radiological findings consistent with PAM, and it can diagnose PAM without the need for invasive procedures. Once diagnosed, screening of all family members for PAM should be done, even when they are asymptomatic, as more than one-third of the cases have a familial pattern.

Familial Aortopathies - State of the Art Review.

Aortopathies are conditions that result in aortic dilatation, aneurysm formation and dissection. Familial aortopathies (perhaps better known as heritable thoracic aortic aneurysm and dissection, h-TAAD, as not all have a positive family history) are recognised to have an underlying genetic cause and affect the aorta, predisposing it to the above pathologies. These conditions can also affect the extra-aortic vasculature, particularly large elastic arteries and other body systems. Mutations in a number of genes have been associated with h-TAAD. However, not all affected families have a pathogenic gene variant identified-highlighting the importance of a three-generational family history and the likely role of both environmental factors and future gene discoveries in furthering knowledge. Survival has improved over the last few decades, essentially due to surgical intervention. The benefit of identifying affected individuals depends upon a regular surveillance program and timely referral for surgery before complications such as dissection. Further research is required to appreciate fully the effects of individual gene variants and improve evidence for prophylactic medical therapy, as well as to understand the effect of h-TAAD on quality of life and life choices, particularly around exercise and pregnancy, for affected individuals. This will be complemented by laboratory-based research that seeks to understand the tissue pathways that underlie development of arterial pathology, ideally providing targets for novel medical therapies and a means of non-invasively identifying individuals at increased vascular risk to reduce dissection, which remains a devastating life-threatening event.

Two monogenic disorders masquerading as one: severe congenital neutropenia with monocytosis and non-syndromic sensorineural hearing loss.

BACKGROUND: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.

Catheter and Device Management of Inherited Cardiac Conditions.

This state-of-the art review discusses sudden cardiac death (SCD) risk stratification and prevention using implantable cardioverter defibrillator (ICD) therapy and the place of catheter ablation in the major inherited cardiomyopathies and primary arrhythmic syndromes. ICD therapy protects against SCD in many inherited cardiac conditions, particularly the cardiomyopathies in advanced stages, such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). However, they are not usually indicated in most patients with cardiac ion channelopathies, particularly long QT syndrome, since medical management is safe and preferable for most cases. The general exception is the secondary prevention setting following a cardiac arrest, where guidelines mostly support ICD therapy. However, in the case of catecholaminergic polymorphic ventricular tachycardia (CPVT), ICD therapy is less clear, with some studies indicating increased mortality when an ICD is used following a cardiac arrest, compared to optimal medical therapy alone. When ICDs are placed, they are commonly associated with morbidity, and do not reduce the burden of ventricular arrhythmias (VA), such that multiple ICD shocks can ensue. Catheter ablation has been shown to reduce VA burden, VA related symptoms and ICD therapy in correctly identified patients in each condition. Its role is particularly important in cases where monomorphic ventricular tachycardia (VT) is prevalent, such as Lamin-related dilated cardiomyopathy (DCM) and ARVC. Evidence is growing to support the use of catheter ablation to treat premature ventricular contraction (PVC) induced VF in the setting of long and short QT syndromes, CPVT, idiopathic VF and early repolarisation syndromes. In Brugada syndrome, epicardial substrate ablation can even apparently eliminate the electrocardiographic (ECG) phenotype and reduce VA burden during follow-up.

How Patient Perceptions Shape Responses and Outcomes in Inherited Cardiac Conditions.

At least one-third of adults living with an inherited cardiac condition report clinically-significant levels of psychological distress. Poorer health-related quality of life compared with population norms is also consistently reported. These outcomes are associated with younger patient age, having an implantable cardioverter defibrillator, and receipt of uncertain clinical test results, and can influence self-management behaviours, such as adherence to potentially critical life-preserving medications. According to the Common Sense Model of Illness, people use information from multiple sources to 'make sense' of their health condition, and how they conceptualise the condition can strongly influence adaptation and coping responses. Previous studies with people with inherited cardiac conditions show that illness perceptions, such as greater perceived consequences and a poorer understanding of the condition, are associated with greater psychological distress and poorer adherence to medication. The Common Sense Model provides one potential framework for identifying patients who may be more vulnerable to adverse health outcomes, and for developing early interventions to reduce the physical and psychosocial burden of these conditions. Interventions based on the Common Sense Model have successfully improved physical and psychosocial outcomes associated with other cardiac conditions, and could be tailored for use with patients with an inherited cardiac condition (ICC).

Autonomic Peripheral Neuropathy.

PURPOSE OF REVIEW: This article provides a summary of the autonomic neuropathies, including neuropathies associated with diabetes mellitus, neuropathies due to amyloid deposition, immune-mediated autonomic neuropathies (including those associated with a paraneoplastic syndrome), inherited autonomic neuropathies, and toxic autonomic neuropathies. The presenting features, diagnostic investigations, and natural history of these neuropathies are discussed. RECENT FINDINGS: Recent findings in autonomic peripheral neuropathy include data on the epidemiology and atypical presentations of diabetic autonomic neuropathy, treatment-induced neuropathy of diabetes mellitus, the presentation of immune-mediated neuropathies, and advances in hereditary neuropathy associated with amyloidosis and other hereditary neuropathies. SUMMARY: Knowledge and recognition of the clinical features of the autonomic neuropathies, combined with appropriate laboratory and electrophysiologic testing, will facilitate accurate diagnosis and management.

Generation of the induced human pluripotent stem cell lines CSSi009-A from a patient with a GNB5 pathogenic variant, and CSSi010-A from a CRISPR/Cas9 engineered GNB5 knock-out human cell line.

GNB5 loss-of-function pathogenic variants cause IDDCA, a rare autosomal recessive human genetic disease characterized by infantile onset of intellectual disability, sinus bradycardia, hypotonia, visual abnormalities, and epilepsy. We generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of a patient with the homozygous c.136delG frameshift variant, and a GNB5 knock-out (KO) line by CRISPR/Cas9 editing. hiPSCs express common pluripotency markers and differentiate into the three germ layers. These lines represent a powerful cellular model to study the molecular basis of GNB5-related disorders as well as offer an in vitro model for drug screening.

Perioperative management of patients with genetic multisystem diseases associated with pre­excitation.

Pre-excitation is associated with life-threatening arrhythmias. Apart from the well-known Wolff-Parkinson-White syndrome, a number of rare diseases are associated with pre-excitation due to the existence of accessory pathways. The present review aims to focus on anaesthesia and perioperative care of patients with rare genetic diseases associated with pre-excitation due to the existence of a bundle of Kent or other accessory pathways. The Danon disease, Fabry disease and Pompe disease, tuberous sclerosis, Leber hereditary optic neuropathy (LHON), and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome are genetic multisystem disorders which may involve pre-excitation, usually combined with cardiomyopathy. The anaesthetic management of the above syndromes may become quite challenging. We conducted a PubMed and manual literature search for all types of relevant publications; we identified 58 articles suitable to be included in the present review. According to the literature, a high index of suspicion for the possibility of pre-excitation is required, and anaesthetic drugs and adjuvants should be chosen carefully, in order to prevent or at least not facilitate arrhythmias associated with accessory pathways. The perioperative management should be further tailored to the specific abnormalities of each condition. Multidisciplinary consultation and care, according to the affected organs, are mandatory for a safe outcome. The anaesthetic plan should be focused on preoperative clinical optimization and on case-specific management, tailored to the various systems involved.