Rare endocrine disease: Still a long and a winding road

I’m very proud to welcome you to this special issue of Endocrine dedicated to rare endocrinological conditions. It marks the 2021 recurrence of RARE DISEASE DAY, which takes place every year on the last day of February 28th. The primary goal of this world-wide initiative is to heighten awareness in our societies of the existence of rare diseases and the impact they have on the individuals living with them and their families. Heightened awareness and understanding not only among the general public but also among policy makers, public health authorities, industry representatives, researchers, and health professionals.

This year’s RARE DISEASE DAY takes place in the shadow of the COVID-19 pandemic, which continues to wreak havoc in virtually all corners of our world, a terribly “perfect storm” that threatens to overwhelm our healthcare systems and nullify many of the efforts made over the years to alleviate suffering. And nowhere, perhaps, is this threat more frightening than among the world’s 300 million vulnerable individuals with diseases so rare that even obtaining a diagnosis can represent a struggle, let alone treatment and ongoing care.

Update on primary bilateral macronodular adrenal hyperplasia (PBMAH)

Primary bilateral macronodular adrenal hyperplasia (PBMAH), characterized by bilateral benign adrenal macronodules (>1 cm) potentially responsible for variable levels of cortisol excess, is a rare and heterogeneous disease. However, its frequency increases due to incidentally diagnosed cases on abdominal imaging carried out for reasons other than suspected adrenal disease. Mostly isolated, it can also be associated with dominantly inherited genetic conditions in rare cases. Considering the bilateral nature of adrenal involvement and the description of familial cases, the search of a genetic predisposition has led to the identification of germline heterozygous inactivating mutations of the putative tumor suppressor gene ARMC5, causing around 25% of the apparent sporadic cases. Rigorous biochemical and imaging assessment are key elements in the management of this challenging disease in terms of diagnosis. Treatment is reserved for symptomatic patients with overt or subclinical Cushing syndrome, and was historically based on bilateral adrenalectomy, which nowadays tends to be replaced by unilateral adrenalectomy or lifelong treatment with cortisol synthesis inhibitors.

Molecular genetic testing strategies used in diagnostic flow for hereditary endocrine tumour syndromes

lthough current guidelines prefer the use of targeted testing or small-scale gene panels for identification of genetic susceptibility of hereditary endocrine tumour syndromes, next generation sequencing based strategies have been widely introduced into every day clinical practice. The application of next generation sequencing allows rapid testing of multiple genes in a cost effective manner. Increasing knowledge about these techniques and the demand from health care providers and society, shift the molecular genetic testing towards using high-throughput approaches.

Alström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity

lström syndrome (ALMS) is a monogenic ultra-rare disorder with a prevalence of one per million inhabitants caused by pathogenic variants of ALMS1 gene. ALMS1 is located on chromosome 2p13, spans 23 exons and encodes a predicted 461.2-kDa protein of 4169 amino acids. The infantile cone-rod dystrophy with nystagmus and severe visual impairment is the earliest and most consistent clinical manifestation of ALMS. In addition, infantile transient cardiomyopathy, early childhood obesity with hyperphagia, deafness, insulin resistance (IR), type 2 diabetes mellitus (T2DM), systemic fibrosis and progressive renal or liver dysfunction are common findings. ALMS1 encodes a large ubiquitously expressed protein that is associated with the centrosome and the basal body of primary cilium.