Endocrine Abstracts

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...

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...

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...

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...

Introduction: Loss of function mutations in SGPL1, a key component of sphingolipid metabolism, are associated with accumulation of sphingolipid intermediates giving rise to a multisystemic disease incorporating primary adrenal insufficiency (PAI) and progressive renal and neurological disease. Sphingolipid accumulation is implicated in mitochondrial pathology.Objective: To investigate the impact of SGPL1 deficiency on mitochondrial morphology/ f...

Background: Growth hormone insensitivity (GHI) is a continuum defined by normal/elevated growth hormone (GH), low IGF-I levels and growth restriction. Non-classical/mild-moderate GHI is poorly characterised and is frequently underdiagnosed. Heterozygous dominant negative (DN) gene variants located in the regions encoding the intracellular/transmembrane domains of the GH receptor cause a ‘non-classical’ GHI phenotype.Hypothesis/Objective: Detail...

Case history: Two unrelated male patients were referred for evaluation of short stature. The first patient aged 16.5 years, had a birth weight of 2.6 kg at term (BWSDS -2.4), height 153 cm (HSDS -3.2) at referral and normal BMI SDS of 0.6. He had early postnatal hypoglycemia, which was conservatively managed, but no other significant clinical history. He had relative macrocephaly and disproportionate short stature. His mother was also short with a similar phenotype (height 147...

Background: Pathogenic IGFI gene mutations causing childhood growth failure are extremely rare. Only five autosomal recessive mutations, one IGFI copy number variant and two heterozygous frameshift mutations are reported. Heterozygous missense IGFI mutations haven’t previously been described.Objectives: To identify and functionally characterise a novel missense IGFI variant in a patient with postnatal growth failu...

Objectives: Noonan Syndrome (NS) is an autosomal dominant multi-system disorder characterised by short stature (SS), distinctive facial features and cardiovascular abnormalities. Mutations in multiple genes regulating the RAS-MAPK pathway have been identified in NS including 5 recently described novel LZTR1 variants. We identified 2 novel LZTR1 variants in patients with features of growth hormone insensitivity and NS. The molecular function of LZTR1 ...

Objectives: The homozygous GHR pseudoexon (6Ψ) mutation leads to aberrant splicing of the GHR gene with clinical and biochemical heterogeneity. We investigated whether the phenotypic variability could be explained by transcript heterogeneity i.e. ratio of abnormal (6Ψ GHR) to normal (WT GHR) transcripts and/or the presence of concurrent defects in other short stature (SS) genes.Methods: 6 Ψ GHR ...