Searchable abstracts of presentations at key conferences in endocrinology

ea0085oc1.1 | Oral Communications 1 | BSPED2022

Defects in QSOX2, a novel regulator of STAT5B nuclear import and transcriptional activity, lead to severe post-natal growth restriction

Maharaj Avinaash , Andrews Afiya , Chatterjee Sumana , Hwa Vivian , Storr Helen

Background: Growth Hormone Insensitivity (GHI) is characterised by short stature and functional IGF-I deficiency associated with normal/elevated GH levels. Marked genetic and phenotypic heterogeneity exist, and heritable defects in GH-IGF-I axis associated pathways account for mild-moderate to severe GHI. We report non-consanguineous twin brothers who present with short stature and bi-allelic mutations in QSOX2 encoding a nuclear membrane protein. Genome-wide associat...

ea0085oc1.2 | Oral Communications 1 | BSPED2022

A rare case of short stature with high total insulin like growth factor 1 (IGF-1) and a novel pregnancy-associated plasma protein A2 (PAPPA2) gene mutation

Chatterjee Sumana , Maharaj Avinaash , Storr Helen , Giri Dinesh

Background: PAPP-A2 is a protease which helps to release IGF-1 from a ternary complex by cleaving the IGF binding proteins (IGFBP-3 and -5). Free IGF-1 subsequently binds to its receptor resulting in cell proliferation and growth. Homozygous loss-of-function PAPPA2 mutations lead to low IGF-1 bioavailability and postnatal short stature (SS). Recombinant human IGF-1 (rhIGF-1) treatment improves height SDS in few patients. We report a patient with SS and high plasma tot...


Splice-site mutations in the melanocortin-2 receptor accessory protein that lead to early-onset familial glucocorticoid deficiency type 2

Qamar Younus , Maharaj Avinaash , Chan Li , Deeb Asma , Metherell Louise

Background: Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency, with preserved mineralocorticoid production. FGD type 2 is caused by mutations in MRAP encoding the melanocortin-2 receptor accessory protein. MRAP has a single transmembrane domain essential to its function in trafficking the MC2R/ACTH receptor. 15 mutations in MRAP have been described, five of which are within the canonical donor splice-site of intro...

ea0095oc8.3 | Oral Communications 8 | BSPED2023

Dysregulated pathways reveal NOVEL mechanistic insights underlying HMGA2-related growth failure in Silver Russell Syndrome

Maharaj Avinaash , Cottrell Emily , Massoud Ahmed , Hwa Vivian , Storr Helen

Background: Silver Russell syndrome (SRS) is a heterogeneous disorder characterised by intrauterine and post-natal growth retardation, relative macrocephaly, protruding forehead, feeding difficulties and body asymmetry. Variants in HMGA2 are a rare cause of SRS and despite strong evidence for the crucial role of HMGA2 in growth regulation, the underlying mechanism underlying growth retardation has, thus far, not been elucidated....

ea0077p11 | Adrenal and Cardiovascular | SFEBES2021

SGPL1 regulates expression of electron transport chain components to modulate cellular metabolism in the adrenal gland

Williams Jack , Smith Chris , Maharaj Avinaash , Kwong Ruth , Hall Charlotte , Metherell Lou , Prasad Rathi

Introduction: Sphingosine-1-phosphate lyase (SGPL1) catalyses the final step in sphingolipid metabolism, irreversibly degrading the lipid signalling molecule sphingosine-1-phosphate (S1P). The relative abundance of S1P compared to its precursors sphingosine and ceramide finely tunes signal transduction for a wide range of cellular pathways including proliferation, apoptosis, migration and calcium handling. Loss-of-function mutations in SGPL1 cause a spectrum of disorders, incl...

ea0077p134 | Adrenal and Cardiovascular | SFEBES2021

In vitro splicing assay proves the pathogenicity of intronic variants in MRAP

Smith Chris , Maharaj Avinaash , Qamar Younus , Read Jordan , Williams Jack , Marimuthu Vidhya , Chan Li , Metherell Lou

Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency with retention of normal mineralocorticoid production. FGD causing mutations in the MC2R accessory protein, MRAP, often occur at the canonical donor splice-site of intron 3, presumed to result in skipping of the first coding exon with unknown consequences at the protein level. DNA from three patients (0 - 6 months) with high ACTH and/or low cortisol levels underwent whole e...

ea0051p010 | Adrenal | BSPED2017

An unusual presentation of congenital lipoid adrenal hyperplasia and novel STAR mutation in two siblings

Andrews Edward , Taylor Carl , Metherell Lou , Buonocore Frederica , Achermann John , Maharaj Avinaash , Davies Justin H

Introduction: Congenital lipoid adrenal hyperplasia (CLAH) is rare and caused by mutations in the steroidogenic acute regulatory (STAR) gene, which is involved in a key step in the synthesis of pregnenolone from cholesterol. Cases typically present in the first days of life with severe adrenal crisis, salt wasting and severely disrupted androgen secretion which may result in sex reversal in 46, XY individuals.Case report: We present a 21-month-o...

ea0085oc5.8 | Oral Communications 5 | BSPED2022

SGPL1 deficiency impairs Leydig cell steroidogenesis and should be considered in 46XY individuals with DSD and adrenal insufficiency

Ming Wai Kwong Ruth , Williams Jack , Maharaj Avinaash V , Metherell Lou , Prasad Rathi

Sphingosine-1-phosphate lyase 1 insufficiency syndrome (SPLIS) is a multisystemic syndrome in which primary adrenal insufficiency (PAI) and steroid resistant nephrotic syndrome predominate, secondary to loss-of-function mutations in SGPL1 (sphingosine-1-phosphate lyase). SGPL1 carries out the irreversible breakdown of sphingosine-1-phosphate, a bioactive sphingolipid intermediate, with implicated roles in various cellular processes. Wider endocrinopathy including gonadal insuf...

ea0066oc4.8 | Oral Communications 4 | BSPED2019

SGPL1 deficiency leads to accumulation of sphingolipid species and downregulation of key enzymes within the steroidogenic pathway

Maharaj Avinaash , Williams Jack , Guran Tulay , Braslavsky Debora , Casas Josefina , Metherell Louise , Prasad Rathi

Background: SGPL1 carries out the final degradative step of the sphingolipid pathway, irreversible cleavage of sphingosine-1-phopshate. SGPL1 deficiency is associated with a pathological accumulation of sphingolipid species and a multi-systemic condition incorporating primary adrenal insufficiency (PAI). Sphingolipid intermediates, ceramide and sphingosine are postulated to act as modulators of the steroidogenic pathway, acting as second messengers altering downstream expressi...

ea0066oc5.9 | Oral Communications 5 | BSPED2019

Rare causes of primary adrenal insufficiency (PAI) in children from Sudan

Qamar Younus , Maharaj Avinaash , Chan Li , AbdulBagi S , Abdullah M , Metherell Louise

Background: Primary adrenal insufficiency (PAI) is a rare, genetically heterogenous condition, characterised by hypocortisolaemia and high plasma ACTH levels in the presence or absence of mineralocorticoid deficiency. PAI can be life-threatening if unrecognised, misdiagnosed or under/untreated. Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive form of PAI characterised by isolated glucocorticoid insufficiency. Mutations in the MC2R/ACTH receptor, ...