Endocrine Abstracts

Introduction: A unique variant of familial glucocorticoid deficiency (FGD) exists in the Irish travelling community, a genetically isolated population with high levels of consanguinity. Affected children develop hypocortisolaemia and raised ACTH but retain normal renin and aldosterone levels. Children also have short stature, evidence of increased chromosomal breakage and natural killer cell deficiency.Methods: We sought areas of homozygosity common to a...

Objectives: Patients with homozygous 6Ψ mutations have GH insensitivity (GHI). We previously described spectrum of clinical and biochemical phenotypes of 11 6Ψ patients (David et al. JCEM 2007;92:655) and now report 9 additional patients. Response to rhIGF-I therapy has not previously been assessed.Methods: 20 6Ψ patients (12 M, 11 families, mean age 4.0±2.2 year) were diagnosed genetically in our centre. Continuous ...

Primary adrenal insufficiency in children can be due to mutations in >20 genes, most commonly CYP21A2, giving rise to 21-hydroxylase deficiency. Phenotypically these disorders overlap and present with conditions ranging from isolated (or familial) glucocorticoid deficiency (FGD) to syndromic disorders involving multiple tissues. Distinguishing between them can be problematic, especially where biochemical testing is not possible or not undertaken. Over the last 30 ...

Background: Primary adrenal insufficiency (PAI) can be associated with significant morbidity in children of all ages, the most common cause being Congenital Adrenal Hyperplasia (CAH). Several other rare inherited causes of PAI have been identified over the years which lack diagnostic phenotypic or biochemical signs, leaving genetic testing as the only approach to make a definitive diagnosis. Our cohort involves >440 patients who presented with features of PAI – hypogl...

Adrenal insufficiency (AI) is life-threatening and can present alone or in combination with other co-morbidities. Here we describe families with a novel association of AI with porphyria caused by biallelic mutations in protoporphyrinogen oxidase (PPOX) or coproporphyrinogen oxidase (CPOX). The porphyrias are a group of disorders caused by defects in one of eight enzymes within the haem biosynthetic pathway, divided into acute porphyrias, resulting in mainly n...

Primary adrenal insufficiency (PAI) in children is usually congenital with more than 25 causal genes leading to overlapping phenotypes. A genetic diagnosis is helpful to guide management and genetic counselling but can be challenging in resource limited settings where facilities for antibodies and genetic testing may be unavailable. Studies from Africa are rare but, in Sudan, the most common genetic aetiologies for PAI are congenital adrenal hyperplasia (CAH; mostly CYP21A...

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 ...

Introduction: Growth Hormone Insensitivity (GHI) is characterised by a triad of short stature (SS), IGF-1 deficiency and normal/high GH levels. ‘Classical’ GHI due to homozygous exonic GHR mutations results in extreme SS with dysmorphic and metabolic abnormalities. Heterozygous exon 9 GHR mutations are rare and exert dominant negative effects due to impairment of GHR dimerization/downstream signalling associated with a milder GHI phenotype. Only sev...

Background: Self-limited DP often segregates in an autosomal dominant pattern, but in the majority of patients the neuroendocrine pathophysiology and its genetic regulation remain unclear. By comparison, many genes have been identified where loss-of-function mutations lead to IHH. Despite likely overlap between the pathophysiology of DP and conditions of GnRH deficiency, few studies have examined the contribution of mutations in IHH genes to the phenotype of DP.<p class="a...

Triple A syndrome (AAAS) is a rare, incurable, homozygous disorder, characterised by tissue-specific degeneration resulting in adrenal failure and neurodisability. The AAAS gene encodes ALADIN, a nuclear pore complex (NPC) protein necessary for nuclear import of DNA protective molecules, important for redox homeostasis. ALADIN’s role is not fully characterised: its discovery at the centrosome and the endoplasmic reticulum suggests a role outside the NPC. The inte...