Molecular confirmation of nine cases of Cornelia de Lange syndrome diagnosed prenatally.

OBJECTIVES: Cornelia de Lange syndrome (CdLS) is characterized by distinct facial features, growth retardation, upper limb reduction defects, hirsutism, and intellectual disability. NIPBL mutations have been identified in approximately 60% of patients with CdLS diagnosed postnatally. Prenatal ultrasound findings include upper limb reduction defects, intrauterine growth restriction, and micrognathia. CdLS has also been associated with decreased PAPP-A and increased nuchal translucency (NT). We reviewed NIPBL sequence analysis results for 12 prenatal samples in our laboratory to determine the frequency of mutations in our cohort. METHODS: This retrospective study analyzed data from all 12 prenatal cases with suspected CdLS, which were received by The University of Chicago Genetic Services Laboratories. Diagnostic NIPBL sequencing was performed for all samples. Clinical information was collected from referring physicians. RESULTS: NIPBL mutations were identified in 9 out of the 12 cases prenatally (75%). Amongst the NIPBL mutation-positive cases with clinical information available, the most common findings were upper limb malformations and micrognathia. Five patients had NT measurements in the first trimester, of which four were noted to be increased. CONCLUSION: We demonstrate that prenatally-detected phenotypes of CdLS, particularly severe micrognathia and bilateral upper limb defects, are associated with an increased frequency of NIPBL mutations.

Complications of percutaneous thoracostomy in neonates and infants.

OBJECTIVE: Percutaneous thoracostomy tubes are widely used in neonates, infants and children. The technique has a low complication rate. Lung perforation by a pigtail catheter is described in a single case report. STUDY DESIGN: This is a multi-center case series of neonates and infants who experienced thoracic organ injury following percutaneous chest tube placement between 2006 and 2015. RESULT: Eleven patients had chest tube-related thoracic organ injury. In six, tubes were placed during resuscitation. Gestational ages ranged from 24+6 weeks to term. Most of the chest tubes were pigtail catheters, and the most common injury was lung lobe perforation. Pericardium and mediastinum were also sites of injury. Some patients had small pleural effusions, with no other complications identified. CONCLUSION: Thoracic organ injury by percutaneous catheters may be more common than previously appreciated. Clinical and radiological findings are non-specific, and the diagnosis may not be apparent until autopsy.

Neuropathology: art and science.

So many examples of computer-designed (rather than human-designed) displays occurred at a recent meeting of the American Association of Neuropathologists that we were stimulated to develop simple guides to help improve presentation. Various color combinations provide examples of the best (and worst) contrast between the message and the medium (background).

Relationship between epidemiologic risk factors and clinicopathologic findings in the sudden infant death syndrome.

The risk of sudden infant death syndrome (SIDS) is said to be enhanced by factors such as prematurity, low birth weight, and perinatal distress. The significance of risk factors for SIDS research was questioned because the majority of SIDS victims seem to lack them. Therefore, postmortem records of 1144 infants who died suddenly and unexpectedly in King County, Washington, over a 25-year period were studied. Deaths were classified as "explained" if a cause was apparent, "classic" SIDS if the history and autopsy were unrevealing or, where the diagnosis of SIDS was doubtful, as "probable" or "possible" SIDS. The infants' birth certificates were compared with those of 3647 infants born during a similar period. Seventy-nine deaths (7%) were explained. The 1065 previously certified as SIDS were reclassified classic SIDS (82%), probable SIDS (13%), and possible SIDS (5%). Low birth weight, small size for gestational age, prematurity, and low 5-minute Apgar scores each form a "continuum"; the possible-SIDS group had the highest proportion of such infants, followed by the probable- and classic-SIDS groups, which exhibit extensive overlap with the control population. A 5-minute Apgar score of less than 7 and delayed postnatal growth rate are not risk factors for classic SIDS. Risk factors are more prevalent in SIDS infants where the diagnosis may be doubtful. The great majority of SIDS victims possess fewer risk factors. To avoid the bias of confounding variables, SIDS research should focus on as "pure" a SIDS population as is possible.

Prenatal growth of the median face.

The growth and development of the median facial region remain incompletely understood. Data concerning the prenatal size and growth rates of facial components are especially lacking. A group of fetuses and newborn infants with apparently normal craniofacial development and body size was therefore studied at autopsy. The interorbital distance and dimensions of the external nose, philtrum (upper lip), and mouth were determined; the growth of morphogenetically related structures--the ethmoid bone and tongue--was also studied. The slopes of linear regressions of these variables against body length indicated that growth of the median facial region proceeds slowly in the latter half of gestation. The center of the face seems to grow slower than the sides of the face. A multivariate technique, factor analysis, identified and ordered relationships among the variables. The best statistical summary of size in the median face was given by four transversely oriented variables, nose breadth, outer orbital distance, inner canthal distance, and mouth width. Within the region, a secondary cluster was dominated by sagittally oriented variables. The second best summary of median facial relationships was provided by three variables of lingual size and was followed by a group of variables representing ethmoidal size. This pattern of growth may represent the effects of a developmental hierarchy. Growth seems to be coordinated along the major axes of the body, with transverse growth controlled more rigidly than sagittal growth. The statistical independence of the three regions suggests that the controls of growth are also separate.

Urinary tract anomalies associated with congenital diaphragmatic defects.

Anomalies of the urinary tract occur in some 13-27% of infants with congenital posterolateral diaphragmatic defect (CDD) and are often severe (renal agenesis, dysplasia, hypoplasia, or hydronephrosis). To test the hypothesis that urinary and diaphragmatic anomalies share elements of pathogenesis, we reviewed 60 autopsy cases of CDD studied at our institution. Sixteen patients (27%) manifested anomalies of the urinary tract: 12 had markedly altered kidneys, 8 of which were unilateral and ipsilateral to the diaphragmatic defect. Among 27 patients free of gross urinary tract anomalies, kidney weights formed a skewed distribution, with most values above published norms for body weight; by analysis of covariance, kidney weight (as a function of body weight) was significantly greater in CDD than in a control population of infants free of chronic illnesses and congenital anomalies who died suddenly and unexpectedly. Differences in glomerular number and diameter could not be identified between the latter groups. In 71% of patients with isolated left CDD, the left kidney was heavier than the right, a reversal of the usual condition in infancy. These findings demonstrate that both marked and subtle changes of the urinary tract in CDD are generally ipsilateral to the diaphragmatic defect and suggest that the pathogenetic mechanisms responsible for urinary and diaphragmatic anomalies may overlap topographically. Aberrant morphogenesis within a developmental field or fields is one explanation for this.

Central nervous system malformations in the CHARGE association.

Of 144 patients with the CHARGE association (literature 136, new patients 8), 47 (33%) had either a postmortem examination (30) or computerized axial tomography scan (17) of the head. Twenty-six of 47 (55%) had definite central nervous system (CNS) malformations; arhinencephaly, with or without other defects (11), holoprosencephaly (2), holoprosencephaly with arhinencephaly (1), other forebrain defects (3), hindbrain defects (3), or other defects (6). The presence of CNS malformation was most strongly associated with choanal atresia. This review demonstrates a predominance of forebrain anomalies, particularly arhinencephaly and holoprosencephaly, which may provide a clue to the mechanism of abnormal morphogenesis involved in CHARGE association.

Duplication 7p in a family with t(7;11): association with anomalies of the anterior cranial base.

Duplication 7p has been observed in association with several balanced translocations. Of eight previously recorded cases, only one exhibited duplication of the entire short arm of chromosome 7. We report on a newborn infant with multiple congenital anomalies and an abnormal chromosome constitution: 46,XX,-11,+der(11),t(7;11) (p11.1;p15.5)mat. The proposita appeared to possess an isolated duplication of the entire short arm of 7. The patient died at age 4 days because of respiratory complications of meconium aspiration. Clinical and postmortem findings included craniocerebral asymmetry, craniosynostosis of a lambdoid suture, arhinencephaly, hypertelorism, anomalies of the ethmoidal portion of the cranial base, large anterior fontanelle, low set ears, ventricular septal defect (VSD), dysplastic tricuspid and pulmonic valves, hypoplastic genitalia, bilateral dislocated hips, and other minor limb malformations.

Diamniotic placentation associated with omphalopagus conjoined twins: implications for a contemporary model of conjoined twinning.

We have studied omphalopagus conjoined twins with a diamniotic monochorionic placenta. Although conjoined twins usually present in a single amniotic sac, one other example of diamniotic placenta has been reported in omphalopagus twins [Weston et al., 1990: Am J Med Genet 37:558-561]. Most theories concerning the pathogenesis of conjoined twinning exclude the possibility of diamniotic placentation. However, Spencer [1992: Teratology 45:591-602] recently elaborated a model for conjoined twinning based on duplication of organizing centers (primitive streaks) during gastrulation. We have considered the fate of embryonic membranes according to this model of omphalopagus twinning and show that diamniotic placentation is a predictable outcome.

Megalencephaly in sudden infant death syndrome.

The fresh brain weights of 79 infants with sudden infant death syndrome (SIDS) were tabulated and compared with expected "normal" brain weights. The series included 47 males and 32 females. Their ages ranged from 8 days to 16 months with a median of 2.5 months. The weights of all these brains were above the 50th percentile for age, and 64 of 79 brains (81%) were above the 95th percentile, including 15 (19%) at or above the 99.9th percentile. The ratio of the brain stem plus cerebellum weight to the whole brain weight of 93 formalin-fixed brains from victims of SIDS showed that the cerebrum was disproportionately heavier in most cases. No gross or microscopic evidence of cerebral edema was noted to account for the heavier weight. The significance of these findings is debatable. The increase in brain weight was less obvious in infants younger than 1 month of age but accelerated after that age. The brain weights of infants with SIDS may represent the really "normal" weights, since these patients were not known to be ill prior to death. If the brain weights of SIDS infants are really heavier than "normal," the possibility must be considered that disproportionately rapid growth of the brain during early infancy may be detrimental to the neural control of the cardiorespiratory system.

A morphometric study of normal and abnormal fetal to childhood tongue size.

The weight, length, width and thickness of 83 normal tongues from patients aged 25 weeks of gestation to 10.5 years were compared statistically with several measures of body and head size and changes described by linear regression; the relationships between measures were examined by partial and least-squares correlation. Sex differences in tongue size were not evident. The tongue doubles in length, width and thickness between birth and adolescence and grows considerably beyond this period. That the major dimensions of the tongue correlated more with head size than body size implies that local factors affect lingual growth more than generalized somatic ones. The weights of 45 tongues thought to be abnormal in size were compared with those of controls. The volume of normal and abnormal tongues was identical to weight, indicating that density remains constant in a variety of conditions. The tongue was abnormally small in hypoglossia hypodactylia and in cleft lip and palate. Tongue weights were within 1 SD of control means in DiGeorge syndrome or oligohydramnios. The tongue was significantly enlarged when protuberant or in anencephaly, CHARGE association and Crouzon syndrome. Anasarca produced a variable degree of enlargement. Concomitant aberrations in the size of the tongue and mandible occurred frequently, but small tongues were not always associated with small mandibles and large tongues were not always observed with large mandibles. Thus, the association of lingual and craniofacial anomalies seems to develop from a number of diverse factors, in addition to biomechanical ones.

Aberrant morphogenesis of the central nervous system.

This overview of congenital defects of the CNS has emphasized pathogenesis. As developmental pathways continue to be elucidated, this approach remains to an extent hypothetical. When, however, an understanding of the features of morphogenesis and dysmorphogenesis helps to indicate time of onset or to elucidate causal factors, important steps toward the prevention of birth defects are taken.

Chest size and symmetry in congenital diaphragmatic hernia.

Infants with congenital diaphragmatic hernia have significantly increased chest circumferences. This implies that intrathoracic volumes are increased as well. Forces produced by the herniated abdominal viscera seem to provide the chief impetus for this change. Other factors may also contribute, for thoracic enlargement is asymmetric and not always ipsilateral to the hernia. The contribution of an enlarged chest to respiratory insufficiency, persistence of the fetal circulation, and hyperinflation is not fully understood, but may have relevance in evaluating new approaches to therapy.

Congenital posterolateral diaphragmatic hernia: associated malformations.

Congenital posterolateral diaphragmatic hernia (CDH) is widely regarded as an isolated defect, but this view is incomplete. We reviewed our clinical and autopsy experience and the literature from the past 25 years in order to catalogue the frequency and clinical importance of additional malformations in patients with CDH. The study showed two broad categories of patients. In the larger group of infants (65 of 108, or 60%), CDH was the only severe defect, apart from those normally associated with the presence of abdominal viscera in the thorax. Thirty-six of these patients (55%) survived. A striking finding among infants with isolated CDH, not previously highlighted in the literature, was cryptorchidism which was present in 30% of males. By contrast, 43 patients (40%) had one or more severe extradiaphragmatic malformations; only six of these infants (14%) survived. Defects in morphogenesis were widespread, heterogeneous, and seemingly related to numerous pathogenetic mechanisms. Most often abnormalities involved the heart, brain, genitourinary system, craniofacial region, or limbs. The high incidence of multiple anomalies in some patients with CDH should influence our investigations into causes and mechanisms. Patients with CDH should be evaluated carefully for additional defects--their presence has a significant impact on management and worsens prognosis.

Left ventricular hypoplasia in congenital diaphragmatic hernia.

Quantitative anatomic study of the hearts of eight infants with left-sided congenital diaphragmatic hernia (CDH) has revealed significantly decreased cardiac mass, due to hypoplasia of the left atrium and ventricle and interventricular septum. These morphologic deficiencies may be a result of compression of mediastinal structures by herniated abdominal viscera during prenatal life. Left ventricular hypoplasia is likely to be an important factor in the pathogenesis of cardiac insufficiency in patients with left CDH.

Pathophysiology of congenital diaphragmatic hernia: I. Renal enlargement suggests feedback modulation by pulmonary derived renotropins--a unifying hypothesis to explain pulmonary hypoplasia, polyhydramnios, and renal enlargement in the fetus/newborn with congenital diaphragmatic hernia.

Survival of newborns with congenital diaphragmatic hernia (CDH) is largely dependent on the severity of pulmonary hypoplasia (PH) present at birth. Intrathoracic compression by the herniated abdominal viscera is thought to be the primary factor involved in the pathogenesis of the PH in CDH. Humoral and/or amniotic pulmonary growth factors (PGF) have been hypothesized to play a role in normal fetal pulmonary development and may be involved in the pathogenesis of CDH as well. The hypothesis of this paper is that growth of the fetal lung is stimulated by a PGF produced by the kidneys, which is modulated by a feedback signal from the lungs, a pulmonary derived renotropin (PDR). In the fetus with CDH, the lungs may be unable to respond to PGF due to compression by the herniated abdominal viscera. Theoretically, PH associated with CDH would maximally stimulate this feedback loop to release more PDR, resulting in continual stimulation of the kidneys and renal enlargement. If such a scheme plays a role in the in utero pathophysiology of CDH, then newborns with CDH should have enlarged kidneys. To investigate this hypothesis, we reviewed 30 autopsy cases of newborns with CDH and analyzed their kidney weights versus body weights, using historical data as control. Kidney weights in CDH cases were greater than the control population in 77% of the cases; 57% of kidney weights were more than one standard deviation above control values. Adjusted group mean kidney weights were 29.8 g (+/- 1.0 SE) in CDH cases and 25.9 g (+/- 1.5 SE) in the control population (P less than .04). These data support our hypothesis and demonstrate that in newborns with CDH and morphologically normal kidneys, there is significant renal enlargement associated with CDH. The presumed mechanism of this renal enlargement, as well as its relationship to normal and aberrant pulmonary growth and regulation are discussed. If such a selective PGF exists, its therapeutic implications for fetuses and newborns with PH are considerable.

Small-intestine length in infants and children.

Small-intestine length from ligament of Treitz to ileocecal valve was measured in 183 infants and children ranging up to 15 years of age. Elongation of the intestine was rapid until crown-heel length was 60 cm and remained constant from 100 to 140 cm of body length. When patients were placed into three general diagnostic categories (congenital heart disease, abdominal lesions, and miscellaneous) no significant differences were found. However, several striking instances of abnormally long or short small intestines were encountered.

The ethmoid bone: implications for normal and abnormal facial development.

Deficiencies of the ethmoid and embryologically related bones of the anterior cranium have been observed in patients with abnormalities in development or placement of the orbits and eyes, nose, upper lip, mouth, and palate. Although these facial anomalies are commonly associated with holoprosencephaly, they may occur in other syndromes or as isolated cases with normocephaly. Such facial alterations represent the consequences of aberrant migration of tissues into the region normally occupied by the ethmoid bone, beginning early in the sixth week of gestation. The subtle interplay of forces involved in the normal development of the median face appears to be mediated by the ethmoid bone. This interaction may be perceived by dividing the ethmoid bone into three functional components which correspond to and operate in each of the major anatomic planes.