Pia Ostergaard

St George's, University of London | SGUL · Molecular and Clinical Sciences Research Institute

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been l...

There remain gaps in our knowledge of hereditary and sporadic causes of hematological malignancy (HM) and bone marrow failure (BMF) that prevent optimal diagnosis, disease surveillance and treatment. Here we report the discovery of ERG as a novel predisposition gene for BMF and HM. ERG is a known oncogene, typically via gene-fusions, leading to dys...

Pathogenic variants in kinesin KIF11 underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association of KIF11 (encoding EG5) with development of the lymphatic system, and how KIF11 pathogenic variants lead to lymphatic dysfunction and lymphedem...

Introduction The lymphatic system has a pivotal role in immune homeostasis. To better understand this, we investigated the impact of Primary Lymphatic Anomalies (PLA) on lymphocyte numbers and phenotype. Methods The study comprised (i) a retrospective cohort: 177 PLA subjects from the National Primary Lymphatic Anomaly Register with clinical and l...

Superficial erythematous cutaneous vascular malformations are assumed to be blood vascular in origin, but cutaneous lymphatic malformations can contain blood and appear red. Management may be different and so an accurate diagnosis is important. Cutaneous malformations were investigated through 2D histology and 3D whole-mount histology. Two lesions...

Generalised Lymphatic Dysplasia (GLD) is characterised by widespread lymphoedema, with at least one of the following: fetal hydrops, intestinal or pulmonary lymphangiectasia, pleural effusions, pericardial effusions and ascites. Satisfactory medical therapies are lacking. A genetic association has been identified that prevents expression or surface...

The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the ‘Rareservoir’, containing the rare variant ge...

Lipedema is a common disorder characterized by excessive deposition of subcutaneous adipose tissue (SAT) in the legs, hips, and buttocks, mainly occurring in adult women. Although it appears to be heritable, no specific genes have yet been identified. To identify potential genetic risk factors for lipedema, we used bioelectrical impedance analysis...

Lipoedema is a chronic adipose tissue disorder mainly affecting women, causing excess subcutaneous fat deposition on the lower limbs with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is currently unclear. A tightly phenotyped cohort of 200 lipoedema patients was rec...

The genetic aetiologies of more than half of rare diseases remain unknown ¹ . Standardised genome sequencing (GS) and phenotyping of large patient cohorts provides an opportunity for discovering the unknown aetiologies ² , but this depends on efficient and powerful analytical methods ³ . We have developed a portable computational and statistical fr...

Dynamic contrast-enhanced magnetic resonance lymphangiography (DCE-MRL) is regularly reported as unable to depict lymphatic vessels in healthy limbs. In this study, we aim to improve lymph vessel conspicuity with appropriate registration and subtraction of a reference baseline image. Five unaffected individuals and a single unilateral primary lymph...

Background Primary lymphoedema (PL) syndromes are increasingly recognised as presentations of complex genetic disease, with at least 20 identified causative genes. Recognition of clinical patterns is key to diagnosis, research and therapeutics. The defining criteria for one such clinical syndrome, ‘WILD syndrome’ ( W arts, I mmunodeficiency, L ymph...

Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the res...

Lipoedema is a chronic adipose tissue disorder mainly affecting women, causing excess subcutaneous fat deposition on the lower limbs with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is currently unclear. A tightly phenotyped cohort of 200 lipoedema patients was rec...

Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identif...

Background Clinical examination and lymphoscintigraphy are the current standard for investigating lymphatic function. Magnetic resonance imaging (MRI) facilitates three‐dimensional (3D), nonionizing imaging of the lymphatic vasculature, including functional assessments of lymphatic flow, and may improve diagnosis and treatment planning in disease s...

Primary lymphedema is a long-term (chronic) condition characterized by tissue lymph retention and swelling that can affect any part of the body, although it usually develops in the arms or legs. Due to the relevant contribution of the lymphatic system to human physiology, while this review mainly focusses on the clinical and physiological aspects r...

Clinicians and scientists at St George's University Hospital have collaborated to develop a classification algorithm for primary lymphatic anomalies. Instruction is offered on how to apply the algorithm in clinical practice to refine the diagnosis of primary lymphedema and guide on genetic testing and management. It can also be used to interpret mu...

Primary lymphatic anomalies may present in a myriad of ways and are highly heterogenous. Careful consideration of the presentation can lead to an accurate clinical and/or molecular diagnosis which will assist with management. The most common presentation is lymphoedema, swelling resulting from failure of the peripheral lymphatic system. However, th...

Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polypos...

We present a decision tree for the investigation of affected pregnancies.

We present a decision tree for the investigation of affected pregnancies.

Introduction: Fetal hydrops describes abnormal fluid accumulation in two or more extravascular fetal compartments. It is a poor prognostic sign in a fetus, and many will not survive to term. Fetal hydrops is a clinical sign rather than a diagnosis and has a multitude of different causes. Areas covered: This review focusses on non-immune fetal hydro...

Background: Primary lymphedema is genetically heterogeneous. Two of the most common forms of primary lymphedema are Milroy disease (MD) and lymphedema-distichiasis syndrome (LDS). This study aims to look further into the pathogenesis of the two conditions by analyzing the lymphoscintigram images from affected individuals to ascertain if it is a use...

Purpose: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity. Design: Retrospective case series. Methods: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained f...

This Article contains an error in the last sentence of the ‘Variant analysis suggests they are pathogenic’ section of the Results, which incorrectly reads ‘No truncated PIEZO1 protein products were identified in western blot analysis in GLD1:II.3 and GLD2:II.2 (Fig. 2, Supplementary Fig. 6), suggesting that the truncated protein is not stable and t...

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during l...

Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR; OMIM 152950) is a rare autosomal dominantly inherited syndrome. Mutations in the kinesin family member 11 (KIF11) gene have been associated with this condition. Here, we report a de novo novel heterozygous missense mutation in exon 12 of the KIF11 gene [c.1402...

PIEZO1 is a large mechanosensitive ion channel protein. Diseases associated with PIEZO1 include autosomal recessive Generalised Lymphatic Dysplasia of Fotiou (GLDF) and autosomal dominant Dehydrated Hereditary Stomatocytosis with or without pseudohyperkalemia and/or perinatal oedema (DHS). The two disorders show overlapping features, fetal hydrops/...

Background: Lack of investigatory and diagnostic tools has been a major contributing factor to the failure to mechanistically understand lymphedema and other lymphatic disorders in order to develop effective drug and surgical therapies. One difficulty has been understanding the true changes in lymph vessel pathology from standard 2D tissue section...

Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation (“organization”) of Prox1 hi endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc...

A homozygous truncating mutation in nonreceptor tyrosine phosphatase 14 (PTPN14) has recently been associated with an extremely rare autosomal recessive syndrome of congenital posterior choanal atresia and childhood-onset lymphedema. PTPN14 has been shown to interact directly with the vascular endothelial growth factor receptor 3 (VEGFR3), a recept...

Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality....

Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hy...

The RASopathies, which include Noonan syndrome (NS) and Cardiofaciocutaneous syndrome (CFC), are autosomal dominant disorders with genetic heterogeneity associated with germline mutations of genes in the Ras/mitogen-activated protein kinase (MAPK; RAS-MAP kinase) pathway. The conditions overlap and are characterised by facial dysmorphism, short sta...

PurposeMicrocephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations.Methods Standard ophthalmic examination and in...

Turner syndrome is a complex disorder caused by an absent or abnormal sex chromosome. It affects 1/2000-1/3000 live-born females. Congenital lymphoedema of the hands, feet and neck region (present in over 60% of patients) is a common and key diagnostic indicator, although is poorly described in the literature. The aim of this study was to analyse t...

We have identified TUBGCP4 variants in individuals with autosomal-recessive microcephaly and chorioretinopathy. Whole-exome sequencing performed on one family with two affected siblings and independently on another family with one affected child revealed compound-heterozygous mutations in TUBGCP4. Subsequent Sanger sequencing was performed on a pan...

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM #152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in sixteen families worldwide. This is a review of the condition based...

Historically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010 we introduced a new...

Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features most commonly affecting the face, eyes, dentition and digits. The condition is caused by mutations in the GJA1 gene on chromosome 6. GJA1 codes for connexin 43, a gap junction protein important in providing cell to cell communication and is expressed in...

Rationale: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. Objective: To investigate the under...

Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detaili...

Microcephaly-lymphedema-chorioretinal dysplasia (MLCRD) syndrome is a rare syndrome that was first described in 1992. Characteristic craniofacial features include severe microcephaly, upslanting palpebral fissures, prominent ears, a broad nose, and a long philtrum with a pointed chin. Recently, mutations in KIF11 have been demonstrated to cause dom...

We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohor...

We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicat...

Ostergaard P, Simpson MA, Jeffery S. Massively parallel sequencing and the identification of genes for primary lymphoedema: a perfect fit. Primary lymphoedema is a clinically and genetically heterogeneous group of disorders characterized by disruption of the lymphatic system. To date, the majority of the causative genes in primary lymphoedema have...

Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital. Linkage analysis...

Four reports have been published on an association between acute myeloid leukaemia (AML) and primary lymphedema, with or without congenital deafness. We report seven new cases, including one extended family, confirming this entity as a genetic syndrome. The lymphedema typically presents in one or both lower limbs, before the hematological abnormali...

Lipedema is a condition characterized by swelling and enlargement of the lower limbs due to abnormal deposition of subcutaneous fat. Lipedema is an under-recognized condition, often misdiagnosed as lymphedema or dismissed as simple obesity. We present a series of pedigrees and propose that lipedema is a genetic condition with either X-linked domina...

Generalised lymphatic dysplasia (GLD) is characterised by extensive peripheral lymphoedema with visceral involvement. In some cases, it presents in utero with hydrops fetalis. Autosomal dominant and recessive inheritance has been reported. A large, non-consanguineous family with three affected siblings with generalised lymphatic dysplasia is presen...

Generalised lymphatic dysplasia (GLD) is characterised by extensive peripheral lymphoedema with visceral involvement. In some cases, it presents in utero with hydrops fetalis. Autosomal dominant and recessive inheritance has been reported. A large, non-consanguineous family with three affected siblings with generalised lymphatic dysplasia is presen...

A 23-year-old male was referred to our clinic with diagnosis of idiopathic isolated growth hormone deficiency. A detailed family history revealed short stature and swelling of legs which only affected females in four generations of his family. Combined pituitary function tests revealed growth hormone deficiency, secondary hypothyroidism and hypopro...

Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary l...

Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary l...

Sexual size dimorphism in the Chondracanthidae is very marked: we investigate whether it is a consequence of dwarfing of males or females becoming giants. Plotting male size against female size indicates that the relationship is allometric, i.e., showing a trend towards increasing sexual size dimorphism. This is supported by the results of an analy...

Feeding habits of tropical fish larvae were analysed in a comparative study of four species (Scorpaenodes sp., Carangoides sp., Acanthocepola sp. and Cynoglossus sp.) from the Andaman Sea. We investigated morphological characteristics and their potential influence on larval feeding, and looked for common patterns in larval prey preference. Gut cont...

Male chondracanthids attach to specific structures located near the genital apertures of the female and the term nuptial organ is proposed for these structures. The morphology of the nuptial organ in Acanthochondria cornuta, A. limandae, Acanthochondrites annulatus, Blias prionoti, Chondracanthodes deflexus, Chondracanthus lophii, Lernentoma aselli...

Male Chondracanthus lophii was studied using light and electron microscopy. Observations on external morphology and internal anatomy are presented. Males possess a full set of functional mouth parts, the digestive system is active and the dominant cell type in the midgut is identified as the vacuolar type B-cell, but the gut is a blind ending sac w...

The status of subfamilies and genera within Chondracanthidae Milne Edwards, 1840 has recently been revised. Forty four genera are currently recognised as valid for the Chondracanthidae and a comprehensive catalogue to the valid genera and species of the family is presented here. In addition, numerous supplementary observations are presented on exis...

The existing systematics of the Chondracanthidae is based predominantly on female characters and divides them into two subfamilies: Chondracanthinae and Lernentominae. Phylogenetic analyses using maximum parsimony were performed using 186 male and female characters. Different trees were generated when male and female characters were analysed separa...

Schistosomes are digenean flukes, parasitic of birds, mammals and crocodiles. The family Schistosomatidae contains species of considerable medical and veterinary importance, which cause the disease schistosomiasis. Previous studies, both morphological and molecular, which have provided a good deal of information on the phylogenetics of this group,...