Differences in the clinical spectrum of two adolescent male patients with Alström syndrome

Abstract

Alström syndrome is a rare disorder typified by early childhood obesity, neurosensory deficits, cardiomyopathy, progressive renal and hepatic dysfunction, and endocrinological features such as severe insulin resistance, type 2 diabetes, hyperlipidemia, and hypogonadism. Widespread fibrosis leads to multiple organ failure. Mutations in ALMS1 cause Alström’s syndrome. Two age-matched, unrelated adolescent males of Serbian descent with Alström syndrome underwent an extensive workup of blood chemistries, and ophthalmological, audiological, and genetic evaluations. Although both showed typical features of Alström syndrome in childhood, several differences were observed that have not been reported previously. Patient 1 was first studied at the age of 13 years for multisystemic disease and re-evaluated at the age of 15.5 years. Patient 2 is a 15-year-old boy who presented at birth with epilepsy and psychomotor developmental delay and generalized tonic–clonic seizures with severe cognitive impairment, features not documented previously in this syndrome. Sequencing analysis indicated two novel ALMS1 mutations in exon 8: p.E1055GfsX4 and p.T1386NfsX15. Metabolic and physiological similarities were observed in both patients, including severe insulin resistance, and truncal obesity with fat loss suggestive of partial lipodystrophy, supporting evidence for a role for ALMS1 in adipose tissue function. The unusual phenotypes of clonic–tonic seizures and severe cognitive abnormalities and lipodystrophy-like adiposity pattern have not been documented previously in Alström syndrome and may be an under-reported abnormality.

Alström Syndrome with Early Vision and Hearing Impairement

“…Kuburović et al ( 2013) [8] reported on a patient with an unusual clinical presentation and a heterozygous ALMS1 pathogenic variant in exon 16, c.10568_10569delAT; p.His-3523Terfs17. The clinical features included centripetal obesity with selective loss of adipose tissue in his legs and gluteal region, acanthosis nigricans, gynecomastia, scoliosis, glomerulopathy, subclinical primary hypogonadism, restrictive filling of the left ventricle, and significant early atrial contraction.…”

“…Their second patient had epilepsy at the age of two years, followed by vision and hearing impairments, hypertension, hepatic dysfunction, mental retardation (IQ 40), hypogonadotropic hypogonadism, renal dysfunction, acanthosis nigricans, and truncal obesity with reduced femoral-gluteal fat. The authors propose that variable neurological involvement, including seizure activity, should be included as a rare occurrence, and as a part of the phenotypic spectrum of ALMS [8].…”

Perspectives in Pediatric Pathology, Chapter 21. Testicular Pathology in Heritable Metabolic Disease

“…In adolescence the testes and penis are small, and the onset of puberty is sometimes delayed. Secondary sexual characteristics are usually normal [142]. The occurrence of normal to high FSH and LH and low testosterone levels suggests primary hypogonadism.…”

Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families

“…AS patients also present short stature, hypogonadotropic hypogonadism in affected males, and polycystic ovarian syndrome (PCOS) in affected females. In AS patients, clinical features may appear at different times throughout childhood followed by progressive multiorgan failure which reduces life expectancy where patients rarely live beyond their 5th decade of life ( 2 ). Although clinical assessment is considered as the first line of diagnosis, gradual multiorgan dysfunction and variable expressivity of the disease within the same family members make it more challenging ( 3 ).…”