Elizabeth McPherson

A marginal illustration of a non‐ambulatory child in the 14th Century Luttrell Psalter is the earliest currently identifiable image of an individual with Split Hand Split Foot with Long Bone Deficiency (SHFLD). Changes in portrayal of SHFLD over the centuries reflect changes in social perception of disabilities from pious sympathy to scientific curiosity and unfortunately also morbid fascination. Hopefully understanding of the past attitudes toward split hand and foot as reflected in art can help in moving toward acceptance of individuals with this highly visible malformation.

The Wisconsin Stillbirth Service Program (WiSSP) provided expert review by a dysmorphologist for community‐acquired data on 3137 fetal deaths between 1983 and 2017. Intrinsic fetal causes were consistently identified in about 25% while placental and maternal causes were recognized with increasing frequency as attention was shifted from a primarily fetal to a multifocal approach. Identification of causes increased from 40% to 78% and in about half of cases results of the review altered recurrence risk and/or future pregnancy management. Banked data from WiSSP formed the basis of 24 publications, more than half of which have a genetic counselor and/or summer premedical student intern as an author. The earlier publications emphasized validation of the concept of community‐based evaluation with central review, the utility of various parts of the WiSSP protocol, the similarity of second‐trimester miscarriages <20 weeks to later stillbirths with respect to causes identified and recurrence risks, and the potential for results of etiologic evaluation to influence future prenatal care. The most important recurrent theme, however, was the interaction of intrinsic fetal, placental, and maternal factors in contributing to fetal demise. This implies that, at least in developed nations with available obstetric care, reduction in stillbirth will require careful attention to the myriad of factors contributing to fetal, placental, and maternal well‐being.

An abnormal fetoplacental (F/P) ratio is a risk factor for poor pregnancy outcomes including fetal death, but studies of F/P ratio among stillbirths are limited. In the Wisconsin Stillbirth Service Program cohort of second and third trimester fetal deaths, 1,022 were at ≥24 weeks with data on fetal and placental weight. Comparison with data for viable infants of the same gestational ages (GAs) showed that the F/P ratio increases more rapidly with GA for stillbirths than for viable infants. While placentas of stillborn infants are small at all GA, weights of deceased fetuses are lowest early in the second trimester, becoming nearly normal by term. Excess high F/P ratios are noted at all GAs, increasing toward term, while low ratios are frequent at early gestation but rare near term. Analysis by cause of death shows that F/P ratios are markedly elevated for placental and maternal causes (about 50% above the 90th centile), somewhat elevated for cord accidents, non‐hydropic fetal, and unknown causes (about 1/3 above the 90th centile), and variable with 40% below the 10th centile for hydropic stillbirths. Across all causes and GAs, placental weights are more abnormal than fetal weights, suggesting that diminished placental function may contribute to fetal demise even when non‐placental causes (e.g., premature membrane rupture, cord accidents, and chromosomal disorders) are identified. About half of all stillbirths have abnormal F/P ratios, suggesting that improvements in prenatal assessment of placental size and function might aid in identifying pregnancies at risk for demise; unfortunately, therapeutic options for ongoing pregnancies with diminished placental function remain limited.

Hydrops fetalis was diagnosed in 277 (9%) of 3,137 fetuses referred to the Wisconsin Stillbirth Service Program (WiSSP) for etiologic evaluation of stillbirth or second trimester miscarriage. Hydrops was clinically recognized at delivery in only about half the cases, while the remainder were diagnosed at autopsy or during evaluation of records, photographs, and radiographs. The peak incidence of hydrops was at 20–28 weeks. Hydropic fetuses were also frequent before 20 weeks but became increasingly rare toward term. The most frequent identifiable underlying cause was chromosomal (29%), followed by other syndromes (14%), and more distantly by cardiac (6%) and other single system disorders. While the overall prevalence of hydrops and chromosomal causes was comparable to other autopsy series, the frequency of nonchromosomal syndromes was higher, reflecting increased attention to syndrome identification. Lethal multiple pterygium syndrome (LMPS) was identified retrospectively in 17 cases, accounting for 6% of all hydrops; 3/17 had a previous affected sib, emphasizing the importance of accurate diagnosis and counseling. Depending on the underlying cause, hydropic fetuses may be either small (if the cause is chromosomal or LMPS) or large (in cases with other syndromes or cardiac causes) for gestational age. The relatively large number in the “idiopathic” group in WiSSP (104/277; 38%) is probably due to variability of autopsies at local hospitals and limited laboratory data. Improved recognition of hydrops and testing directed at diagnosis of specific underlying causes can lead to improved counseling for families.

Twins, particularly monochorionic (MC) pairs, are at increased risk for fetal death. Whereas previous work has sought to understand the mechanisms for this increased mortality, most studies analyze viable twin pregnancies or liveborn twin cohorts. In the Wisconsin Stillbirth Service Program cohort of 3,137 stillbirths and second trimester miscarriages, we identified 175 twin pregnancies for a twinning rate of 56/1,000, which is approximately double the general population. The excess of twins among miscarriages and stillbirths was attributable to MC pairs as the incidence of dizygotic (DZ) twinning was not increased compared to livebirth data. The leading causes of fetal demise among twins were twin–twin transfusion, acardia, and twin–twin disruption. Maternal causes of death, primarily premature rupture of membranes, were moderately increased in both MC and DZ twins relative to singletons. Although deceased twins were smaller than expected for viable twins at comparable gestational ages, placenta weights of deceased MC pairs were large compared to combined fetal weight, which indicates placental inefficiency likely due to vascular shunting. Co‐twin survival was much lower for MC than for DZ pairs. Therefore, earlier diagnosis and treatment of MC twinning complications may decrease prenatal mortality.

Background: Although autopsy is a key component of the etiologic evaluation following fetal and early neonatal death, and traditionally has been the preferred method to determine the cause of death, an alternative may be suitable when traditional autopsy by a perinatal pathologist is not available or declined.Methods: Among 3137 cases evaluated through the Wisconsin Stillbirth Service Program (WiSSP), a community‐based program for etiologic evaluation of second trimester miscarriage, stillbirth, and early neonatal death, most diagnoses are based on multiple types of data including placental pathology, clinical examination, photographs, maternal records, radiographs, and laboratory testing.Results: Cases in the WiSSP cohort without autopsy have nearly the same overall rate of diagnosis as those with traditional autopsy (56% vs. 58%). Review of the literature shows that although recent systematic protocols including autopsy, placental pathology and genetic studies yield a definite or probable diagnosis in 70% or more, both healthcare providers and families desire less invasive options. Several minimally invasive protocols substituting imaging, primarily MRI, for traditional autopsy have been proposed, but the numbers of deaths evaluated are still very small.Conclusion: We join others who have promoted the benefits of a targeted or less invasive protocol to study perinatal deaths, and emphasize integration of clinical data, selective imaging, genetic testing, and parental counseling. Birth Defects Research 109:1430–1441, 2017.

The 3,003 women referred to the Wisconsin Stillbirth Service Program following a stillbirth or second trimester fetal death reported a total of 4,563 previous pregnancies including 180 previous second or third trimester losses for a total precurrence rate of 3.95%. The 142 women with a history of at least one previous stillbirth and/or late miscarriage differed significantly from the entire cohort with respect to timing and cause of their losses. Women experiencing multiple losses frequently had both second trimester miscarriages and stillbirths >20 weeks but did not have an increased risk of first trimester miscarriage. Recurrences were more likely to be in the second trimester (52% vs. 37%) and to have a maternal (20% vs. 11%) or placental (27% vs. 19%) cause. While fetal causes overall were less common in the group with recurrence (18% vs. 27%), the difference was due mainly to fewer common aneuploidies and other low recurrence risk conditions. Not only known recessive conditions but also “idiopathic hydrops” and multiple congenital anomalies not fitting a known syndrome were more frequent than expected, suggesting that these groups should be investigated for underlying genetic causes that might have been overlooked. Women with second trimester losses and/or a maternal or placental cause of death face significantly higher empiric risks (7–8% vs. 4% for the entire cohort) and should be counseled accordingly. Study of recurrent fetal loss can help identify high risk women who may benefit from treatment and preventive strategies in the future.

In humans, Mammalian Target of Rapamycin (MTOR) encodes a 300 kDa serine/ threonine protein kinase that is ubiquitously expressed, particularly at high levels in brain. MTOR functions as an integrator of multiple cellular processes, and in so doing either directly or indirectly regulates the phosphorylation of at least 800 proteins. While somatic MTOR mutations have been recognized in tumors for many years, and more recently in hemimegalencephaly, germline MTOR mutations have rarely been described. We report the successful application of family-trio Diagnostic Exome Sequencing (DES) to identify the underlying molecular etiology in two brothers with multiple neurological and developmental lesions, and for whom previous testing was non-diagnostic. The affected brothers, who were 6 and 23 years of age at the time of DES, presented symptoms including but not limited to mild Autism Spectrum Disorder (ASD), megalencephaly, gross motor skill delay, cryptorchidism and bilateral iris coloboma. Importantly, we determined that each affected brother harbored the MTOR missense alteration p.E1799K (c.5395G>A). This exact variant has been previously identified in multiple independent human somatic cancer samples and has been shown to result in increased MTOR activation. Further, recent independent reports describe two unrelated families in whom p.E1799K co-segregated with megalencephaly and intellectual disability (ID); in both cases, p.E1799K was shown to have originated due to germline mosaicism. In the case of the family reported herein, the absence of p.E1799K in genomic DNA extracted from the blood of either parent suggests that this alteration most likely arose due to gonadal mosaicism. Further, the p.E1799K variant exerts its effect by a gain-of-function (GOF), autosomal dominant mechanism. Herein, we describe the use of DES to uncover an activating MTOR missense alteration of gonadal mosaic origin that is likely to be the causative mutation in two brothers who present multiple neurological and developmental abnormalities. Our report brings the total number of families who harbor MTOR p.E1799K in association with megalencephaly and ID to three. In each case, evidence suggests that p.E1799K arose in the affected individuals due to gonadal mosaicism. Thus, MTOR p.E1799K can now be classified as a pathogenic GOF mutation that causes megalencephaly and cognitive impairment in humans.