Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management

Abstract

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

“…PPARG, PIK3R1, INSR; Figure 3C), which is more than what expected by chance given the prevalence of monogenic insulin resistance genes in the genome (observed percentage 0.54% [3 out of a total of 553 genes in the 53 loci], expected percentage 0.064%, two-tailed binomial p=0.0056). The PIK3R1 gene encodes regulatory subunits of a critical kinase involved in proximal insulin signalling and rare, loss-of-function mutations in this gene are associated with SHORT syndrome, a dysmorphic condition characterised by short stature, partial lipodystrophy and insulin resistance 40–43. To date, such mutations have been identified in few families worldwide and data from Exome Aggregation Consortium show this gene to have decreased tolerance of missense variation (Z=2.42) and to be particularly intolerant of loss-of-function mutations (pLI=1; Exome Aggregation Consortium, Cambridge, MA, URL: http://exac.broadinstitute.org accessed 22 nd March 2016).…”

Metformin paradoxically worsens insulin resistance in SHORT syndrome

“…In women of reproductive age (like in our case), presentation of the SHORT syndrome may also mimic classical polycystic ovary syndrome [4]. The precise cause of such profound and paradoxical worsening of glucose tolerance post metformin remains unknown.…”

“…on metformin treatment) had not been performed, then subsequent worsening of glucose tolerance, or even early development of type 2 diabetes would have been most likely attributed to beta-cell exhaustion due to genetically-determined insulin resistance, rather to superimposed effects of metformin treatment, that would have been missed. In case of the SHORT syndrome, most available literature data [1, 2, 4, 12, 13] pertain to either genetic or clinical characteristics of disease with hardly any data on treatment modalities and outcome. For instance, in an extensive genetic paper by Huang-Doran et al [14], it is mentioned that “treatment with metformin and combined cyproterone acetate/ethinylestradiol preparation was begun”, however, without any data on treatment outcome.…”

“…In all three family members the diagnosis was made at the Department of Dentistry at the Medical University of Lodz (Poland), where delayed dentition and enamel hypoplasia associated with facial gestalt (triangular face with deep set eyes and prominent forehead in both children and their father) i.e. typical features associated with the SHORT syndrome as described by Avila et al [4], prompted referral to the Department of Genetics. Genetic testing (MEDGEN Warsaw) confirmed mutation in PIK3R1 locus (NM_181523.2:c.1945C > T)—copy of original report available on request.…”

“…SHORT syndrome is also characterized by partial lipodystrophy and severe insulin resistance (IR), leading to an early onset of type 2 diabetes, due to immediate post-receptor defect in insulin signaling (phosphoinositide-3-kinase regulatory subunit 1-PIK3R1) [2, 3]. According to the most comprehensive overview of SHORT syndrome [4], the cardinal feature of this condition include facial gestalt as well as growth and endocrine abnormalities (including clinical presentation of polycystic ovary syndrome).…”