Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship

Abstract

Objective: To describe the clinical and biochemical features, and perform molecular analysis for candidate abnormalities in a novel familial syndrome of intrauterine growth retardation (IUGR), failure of an adolescent growth spurt with proportional adult short stature, minimal subluxation of the 5th metacarpal-phalangeal joint, and adult-onset insulin-resistant diabetes unrelated to obesity or other manifestations of metabolic syndrome (MS). Design: Detailed clinical history, auxological, biochemical, radiological, and molecular studies, including DNA analysis and in vitro study of the GH/IGF1 pathway. Materials and methods: Ten affected adults from two generations of five related families were studied in detail, and information obtained about nine other likely affected individuals. Results: Height Z-scores ranged from K7.3 to K3.8. Unaffected parents of the older generation and frequency of confirmed and suspected instances of the syndrome in the two generations studied is consistent with autosomal recessive inheritance. Insulin resistance was uniformly present in seven subjects tested who were not taking insulin. Diabetes severity did not correlate with overweight. Subjects did not have other typical manifestations of MS such as substantial hyperlipidemia, osteoporosis, or hypertension. No biochemical abnormality in the GH/IGF1 axis or molecular defect was found. Conclusions: While the association of IUGR and adult MS, including diabetes, has been well documented, these subjects did not have typical manifestations of MS. Abnormalities in common components that could result in a combination of IUGR, severe postnatal growth, and insulin resistance have been ruled out. A mutation in an unidentified gene may affect intrauterine and postnatal growth, with insulin resistance directly affected or as a result of this growth phenomenon.

A Novel Variant inCDKN1CIs Associated With Intrauterine Growth Restriction, Short Stature, and Early-Adulthood-Onset Diabetes

“…Our data expand the range of phenotypes observed with CDKN1C defects and suggest that CDKN1C mutations may represent a novel monogenic form of diabetes. (J Clin Endocrinol Metab 99: E2117-E2122, 2014) W e previously reported an extended pedigree from Ecuador whose family members exhibited intrauterine growth retardation (IUGR), failure of an adolescent growth spurt with proportional adult short stature, minimal subluxation of the fifth metacarpal-phalangeal joint, and adult-onset diabetes unrelated to obesity or other manifestations of metabolic syndrome (1). Targeted genomic sequencing failed to identify a shared mutation among five affected family members in candidate genes of the GH/IGF-1 pathway.…”

Exposure to placental insufficiency alters postnatal growth trajectory in extremely low birth weight infants

“…[1][2][3] Postnatal early parenteral nutrition starting at birth and fortifying enteral nutrition with protein both play key roles in postnatal growth of extremely low birth weight (ELBW) infants. [4][5][6][7][8][9][10] Postnatal growth has been associated with neurodevelopmental outcomes, with or without adjusting for common comorbidities of prematurity, emphasizing long-term benefit of optimal growth in the immediate postnatal period. [11][12][13][14] Despite these efforts and recommendations, suboptimal postnatal growth continues to be a major issue in infants born less than 1500 g, especially those who are born less than 1000 g. 3,[14][15] A recent report based on the Vermont Oxford Network database found over 50% of infants born less than 1000 g had a discharge weight below the 10th percentile on the Fenton Growth Chart.…”