Glycemic targets in pregnancies affected by diabetes: historical perspective and future directions.

The definition of optimal glycemic control in pregnancies affected by diabetes remains enigmatic. Diabetes phenotypes are heterogeneous. Moreover, fetal macrosomia insidiously occurs even with excellent glycemic control. Current blood glucose (BG) targets (FBG ≤95, 1-h post-prandial <140, 2 h <120 mg/dL) have improved perinatal outcomes, but arguably they have not normalized. The conventional management approach has been to replicate a pattern of glycemia in normal pregnancy. Although these patterns are lower than previously appreciated, a randomized controlled trial (RCT) has never compared current vs. lower glucose targets powered on maternal/fetal outcomes. This paper provides historical context to the current targets by reviewing evidence supporting their evolution. Using lower targets (FBG <90, 1 h <122, 2 h <110, mean BG ≤95 mg/dL) may help normalize outcomes, but phenotypic differences (type 1 vs. type 2 vs. gestational diabetes) might require different glycemic goals. There remains a critical need for well-designed RCTs to confirm optimal glycemic control that minimizes both small for and large for gestational age across pregnancies affected by diabetes.

The Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. 1984.

INTRODUCTION: The ensuing paper by Professor Giovanni Neri and colleagues was originally published in 1984, American Journal of Medical Genetics 19:195­207. The original article described a new family with a condition that the authors designated as the Perlman syndrome. This disorder, while uncommon, is an important multiple congenital anomaly and dysplasia syndrome; the causative gene was recently identified. This paper is a seminal work and is graciously republished by Wiley-Blackwell in the Special Festschrift issue honoring Professor Neri. We describe a familial syndrome of renal dysplasia, Wilms tumor, hyperplasia of the endocrine pancreas, fetal gigantism, multiple congenital anomalies and mental retardation. This condition was previously described by Perlman et al. [1973, 1975] and we propose to call it the "Perlman syndrome." It appears to be transmitted as an autosomal recessive trait. The possible relationships between dysplasia, neoplasia and malformation are discussed.

Macrosomia and ambiguous genitalia: a long overdue answer to the citizens of Frusino.

In the literature of the Roman Era, a case of macrosomia and genital ambiguity in a newborn is described. Textual evidence concerning this case of androgynism and its symbolism is provided in the present study. Medical interpretation of such cases covers the entire spectrum of differential diagnosis of macrosomia concurrent with genital ambiguity. Female pseudohermaphroditism may be excluded from the differential diagnosis, as the adrenal cortex physiology of the female fetus renders the concurrence of overgrowth and androgen excess unlikely. It will therefore have been a case of 46XY disorder of sexual differentiation due to either fetal overgrowth syndromes (Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes) or to mutations of the WT1 gene. Mutations of the WT1 gene are considered as the most probable diagnosis, resulting in genital ambiguity and macrosomia due to additional altered insulin-like growth factor I (IGF-I) and IGF-II action.

Prediabetes and the big baby.

The concept of prediabetes has come to the fore again with the worldwide epidemic of Type 2 diabetes. The careful observations of W. P. U. Jackson and his colleagues in Cape Town, South Africa 50 years ago still deserve attention. Maternal hyperglycaemia cannot be the only cause of fetal macrosomia, and the pathophysiological reason for the unexplained stillbirth in late diabetic pregnancy still eludes us. The biochemical concepts of 'facilitated anabolism' and 'accelerated starvation' were developed by Freinkel as explanations of the protective mechanisms for the baby during the stresses of pregnancy. Some of these nutritional stresses may also occur in the particular form of early childhood malnutrition known in Africa as kwashiorkor, where subcutaneous fat deposition, carbohydrate intolerance, islet hyperplasia and sudden death may follow a period of excess carbohydrate and deficient protein intake. Different feeding practices in different parts of the world make comparisons uncertain, but there is evidence for insulin resistance in both the macrosomic fetus of the hyperglycaemic mother and in the child with established kwashiorkor. These adaptive changes in early development may play both a physiological and a pathological role. Worldwide studies of hyperglycaemia in pregnancy are gradually establishing acceptable diagnostic criteria, appropriate screening procedures and an evidence base for treatment. Nevertheless the challenge of prediabetes and the big baby is still with us--in Jackson's words--'diabetes mellitus is a fascinating condition-the more we know about it the less we understand it'.

The Helena syndromes.

The author gives a personal account on how he was introduced to the field of clinical genetics as a student of John Opitz in Helena, MT. That process was facilitated by the study of several malformation syndromes. Particularly instructive were the approaches to the cardio-facio-cutaneous, the Perlman, and the FG syndrome. These three conditions are briefly revisited with a critical perspective, made possible by the elapse of 20 years, since the time when the author became acquainted with them.

A historical perspective on gestational diabetes.

Extreme fetal macrosomia occurred in the first recorded case of diabetes in pregnancy in 1823. The belief that the diabetic condition was in some way a symptom of the pregnancy, which dates to that first report, has led to the more recent concept of gestational diabetes. Lesser degrees of maternal hyperglycemia were also recognized to be a risk to the baby, and early studies of carbohydrate intolerance in pregnancy in Boston and Los Angeles have set the stage for the worldwide interest in this maternal/fetal interaction.