Inverted duplication of the distal short arm of chromosome 3 associated with lobar holoprosencephaly and lumbosacral meningomyelocele.

A fetus with lobar holoprosencephaly and lumbosacral meningomyelocele associated with duplication of the short arm of chromosome 3 is reported. The anomalies were detected on fetal ultrasound at 20 weeks' gestation and the autopsy findings correlated well with the prenatal findings. The fetal karyotype was 46,XY,der(3)del(3)(p26) dup(3)(p26p21.3). The association of holoprosencephaly with duplication 3p is well known, but to the best of our knowledge this is the first reported association of meningomyelocele with 3p duplication. These findings suggest that a gene or genes with a crucial role in central nervous system development are located on the short arm of chromosome 3.

Gonadoblastoid testicular dysplasia in Walker-Warburg syndrome.

Two male fetuses (18 and 22 weeks gestation) and a 3-month-old male infant (full sibling of the younger fetus) who were diagnosed with Walker-Warburg syndrome (WWS) on the basis of neuropathologic autopsy findings in brain, eyes, and muscle also had micro-orchia and, microscopically, diffuse gonadoblastoid dysplasia in the testes. Both fetuses also had a miniature left ureter and cystic dysplastic left kidney. Testes from control fetuses of 17-24 weeks gestation with normal karyotype and no central nervous system abnormalities (group A, n = 50), a variety of central nervous system abnormalities (group B, n = 50), or an autosomal aneuploidy syndrome with or without central nervous system abnormalities (group C, n = 30) had no diffuse dysplasia, although a single gonadoblastoid seminiferous tubular profile was present in three controls. Testicular morphology was normal in older fetuses and infants with a wide variety of central nervous system malformations (group D, n = 50). We found no evidence of hypogonadotrophic hypogonadism in the three WWS cases to account for the small penis and incompletely descended testes commonly reported in this condition. We concluded that the apparent specificity of the gonadoblastoid testicular dysplasia to WWS suggests that the gene defect directly affects testicular development.

Partial tetrasomy with triplication of chromosome (5) (p14-p15.33) in a patient with severe multiple congenital anomalies.

We report on a newborn infant with a de novo triplication of the distal segment of 5p: 46,XX,trp(5) (pter-->p14::p14-->p15.33::p15.33--> qter) and multiple congenital anomalies consistent with triplication of 5p. Partial triplication was documented by fluorescence in situ hybridization with a cosmid probe specific for 5p15.2 and microdissected probes obtained from "5pter." Partial duplication of the short arm of chromosome 5 is associated with a specific phenotype that appears to be dependent on the chromosomal region duplicated. Duplication of 5p with breakpoints proximal to band p14 is generally associated with distinct craniofacial malformations, cardiac, renal, intestinal, and limb defects, and mental retardation, whereas duplications with breakpoints distal to 5p14 result in a milder phenotype characterized by minor facial anomalies, developmental delay, and seizures. The most proximal breakpoints of the partial triplication in this patient was estimated to be 5p14, suggesting that a more severe phenotype can occur with triplication of the more distal segment.

Distribution of endoglin in early human development reveals high levels on endocardial cushion tissue mesenchyme during valve formation.

Endoglin is a component of the receptor complex for transforming growth factor (TGF)-beta1 and TGF-beta3. We analysed its expression by immunohistochemistry in human embryos at 4-8 weeks of gestation and in hearts ranging from 4-13 weeks old. We compared endoglin distribution with that of TGF-beta receptors type I (TbetaR-I), type II (TbetaR-II) and betaglycan. Endoglin was found on endothelial cells in all tissues examined, consistent with its expression in adult blood vessels. TbetaR-I, TbetaR-II and betaglycan were observed on most cell types and had an overall similar pattern of distribution. Endoglin was detected on the endocardium as early as 4 weeks, but was absent from myocardium. It was present at high levels on the endocardial cushion tissue mesenchyme from 5-8 weeks' gestation, during heart septation and valve formation, and subsequently decreased as the valves matured. Endoglin expression in heart extracts was confirmed by Western blot analysis. TbetaR-I, TbetaR-II and betaglycan were mostly found on cardiac myocytes, but were detectable at low levels on endocardium. They were expressed transiently on cushion mesenchyme, albeit at much lower levels than endoglin. All four components of the TGF-beta receptor complex were detected by RT-PCR in embryonic heart. Thus transient up-regulation of the components of the TGF-beta receptor complex, and particulartly of endoglin, is associated with heart septation and valve formation during early human development.

Diagnosis and management of stenotic aorto-arteriopathy in childhood.

Stenotic aorto-arteriopathy is an uncommon vascular lesion characterized by segmental arterial stenoses. We reviewed the experience with several management algorithms to define the most effective management course. The clinical records of 14 pediatric patients with acquired SAA who presented over a 16-year period were reviewed. Most patients presented with a mid-thoracoabdominal coarctation and were diagnosed with Takayasu arteritis. Differentiating between Takayasu arteritis and fibromuscular dysplasia was difficult on clinical grounds or by angiography. Medical management of the end-organ disease and renovascular hypertension was only palliative. Selective percutaneous transluminal balloon angioplasty of the stenotic renal arteries had only transient benefits; renal autotransplantation had slightly better success. Dilation of stenosed aortic segments with balloon-expandable endovascular stents and subsequent renal autotransplantation proved useful. Distinguishing SAA resulting from fibromuscular dysplasia caused by Takayasu arteritis in the chronic vaso-occlusive phase may be unnecessary for effective treatment. Therapy should focus on interventions to minimize the end-organ damage caused by the vaso-occlusive manifestations of the disorders.

Skeletal dysplasias with gracile bones: three new cases, including two offspring of a mother with a dwarfing condition.

We describe 3 new cases of a rare form of dwarfism (so-called "lethal skeletal dysplasia with gracile bones" or "osteocraniostenosis"), a condition characterized by thin, brittle bones and death in late gestation or early neonatal life. The first was a 37-week gestation female who died at delivery. She had facial anomalies and positional abnormalities of the hands and feet. The others were male stillborn sibs, who died in utero in the third trimester. Their mother had an undiagnosed dwarfing condition associated with body asymmetry, microcephaly, and unusual facial appearance. Both fetuses were documented by ultrasound to have short limbs and probable long bone fractures late in the second trimester. At autopsy, one fetus had no spleen and the other a hypoplastic spleen. Radiographically, all three cases had very thin diaphyses, diaphyseal fractures, and thin ribs and clavicles. In contrast to the first case who had a normally mineralized calvaria, the sibs had grossly deficient calvarial mineralization. Microscopically, endochondral ossification was qualitatively normal but quantitatively deficient in all three cases. The long bones, especially those of the sibs, lacked the well-defined outer cortex in the mid-shaft normally seen by the third trimester. This failure of organization into the cortex and medulla suggests a failure of bone remodelling. Given the variable presentation in these cases, "lethal skeletal dysplasia with gracile bones" is probably a heterogeneous disorder. The recurrence in one family suggests that the mother has somatic/germline mosaicism of a lethal gene, expressed clinically as growth failure and asymmetry.

Cockroach: the omnivorous scavenger. Potential misinterpretation of postmortem injuries.

Interpretation of postmortem injuries, including their differentiation from those produced antemortem, may be difficult even for experienced forensic pathologists. A variety of animals or insects residing in the death environment may alter the appearance of the deceased. Dictyoptera blattaria (the cockroach) is common in the residential setting. Three cases of sudden and unexpected infant death are presented in which postmortem injuries inflicted by cockroaches initially raised concern of nonaccidental injury. The true nature of the lesions was not recognized by the people at the death scene and, in one case, observation of neck injuries raised suspicion of possible strangulation. In another, the lesions were thought to be burns of different ages. Cockroaches are omnivorous scavengers that devour keratin. They will bite human flesh in both the living and dead with resultant injury. Recognition of cockroach bites will help in the evaluation of injuries discovered during child death investigations.

Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia.

A complex vascular abnormality in the lungs, termed alveolar capillary dysplasia (ACD) and misalignment of the lung vessels, has been recently recognized in some infants with persistent pulmonary hypertension. These infants die despite maximal medical support including extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide has been reported to improve oxygenation in neonates with persistent pulmonary hypertension of the newborn, and may allow some infants to avoid the need for ECMO. We identified five infants who had received inhaled nitric oxide to treat refractory hypoxemia caused by persistent pulmonary hypertension of the newborn, and who subsequently died and had autopsy confirmation of ACD. Each infant received care at a different medical center. In each patient, inhaled NO increased the arterial partial pressure of oxygen dramatically. Despite initial clinical improvement, the response to NO was not sustained in any patient. As responsiveness was lost, each infant with ACD required inhaled NO concentrations of 80 ppm or higher to sustain oxygenation. Each infant died, four after extensive periods of ECMO support. This experience demonstrates that a short-term improvement after inhalation of nitric oxide does not lead to long-term survival in ACD. Further, in three infants the diagnosis of ACD was established by lung biopsy before death. Increasing awareness of this clinical entity may allow for the avoidance of costly, invasive procedures such as ECMO until more specific therapies become available.

Limb defects in homozygous alpha-thalassemia: report of three cases.

Homozygosity for the South-Asian alpha-thalassemia (--SEA/) deletion is a serious hematological condition that results, in most cases, in intrauterine or postnatal death due to anemia and severe hypoxia of prenatal onset. A relationship between congenital abnormalities and intra-uterine hypoxia has been postulated. However, since homozygosity for the (--SEA/) deletion is most common in underdeveloped countries where detailed autopsies are lacking, the incidence of congenital abnormalities among these babies has not been well delineated. We report on three newborn infants, homozygous for the (--SEA/) deletion, who were born with limb defects. We postulate that this combination is the result of prenatal hypoxia which may affect other fetal body organs. This should be taken into consideration when prenatal treatment of affected fetuses, with intrauterine blood transfusion, is suggested.

Alveolar capillary dysplasia: lung biopsy diagnosis, nitric oxide responsiveness, and bronchial generation count.

Alveolar capillary dysplasia, a rare cause of neonatal pulmonary hypertension characterized by a developmental abnormality in the pulmonary vasculature, was diagnosed by lung biopsy in a male newborn maintained on nitric oxide therapy for 18 days. Autopsy confirmed the pulmonary vascular defect and demonstrated deficient airspace formation. In addition, a bronchial generation count was low, suggesting that the abnormal lung vascular development in this condition represents a special form of pulmonary hypoplasia that starts in early fetal life.

Brachydactyly-short stature-hypertension (Bilginturan) syndrome: report on two families.

We report on two families with autosomal dominant brachydactyly of hands and feet and hypertension. All affected members of the first family had proportionate short stature. However, the propositus and the affected relatives in the second family were only short compared to unaffected relatives. The hypertension was medically responsive in all cases. The propositus in the second family had poor compliance and a striking generalized vasculopathy. All patients were of normal intelligence and had a normal facial appearance. The brachydactyly-short stature-hypertension syndrome was first reported by Bilginturan et al. [1973] in a Turkish family and the families reported by us are Caucasian and Hispanic. The gene causing this condition in the original Turkish family was recently mapped to 12p. Our report expands our existing knowledge and the ethnic diversity of this syndrome.

Tissue iron storage patterns in fetal hydrops associated with congestive heart failure.

To learn whether fetal congestive heart failure causes a characteristic tissue iron storage pattern, we selected 15 neonatal autopsy cases of hydrops fetalis in which both the clinical and gross autopsy findings suggested intrauterine congestive heart failure. The latter appeared to be due to functional causes in 10 (3 nonhemolytic anemia, 4 cardiac dysrhythmia, 3 dilated cardiomyopathy) and was associated with cardiac malformation in 5. We graded the amount of hepatocellular siderosis, reticuloendothelial siderosis, and renal tubular siderosis in Perls-stained microscopic sections of liver, spleen, and kidney and compared the iron storage pattern with that in 15 normally developed neonatal autopsy controls (4 preterm, 11 term) and a further 7 with hemolytic anemia (5 alpha-thalassemia, 2 parvovirus B19 infection). Liver cell siderosis was absent in the three cases with nonhemolytic anemia. It was increased in 11 of the remaining 12 cases, as in hemolytic anemia controls. Among the five cardiac malformation cases, three had proximal renal tubular siderosis (as in hemolytic anemia controls) attributed to turbulent blood flow through the heart. Among the five, hydrops appeared to be due to prenatal closure of the foramen ovale in one and to prenatal constriction of the ductus arteriosus in another. In one of the five, and despite complex malformation of the heart, hydrops appeared to be due to complete heart block. We concluded that, although clinical information and morphologic assessment of the heart were basic to identifying a cardiac cause of fetal hydrops, histologic assessment of the pattern of iron storage helped confirm the pathologic diagnosis. Analysis of the pathologic findings led to a scheme for categorizing cardiogenic fetal hydrops.

Development of the respiratory diaphragm in childhood: diaphragmatic contraction band necrosis in sudden death.

The authors studied the respiratory diaphragm in 50 normally grown infants and children aged 1 to 16 years at the time of sudden death. By comparing the weights of both costal diaphragm and heart with age and height, the authors found that the diaphragm grows proportionately to the body as a whole and to the heart in particular. Diaphragmatic contraction band necrosis was found in 15 cases (30%). The incidence was similar in subjects dying of asphyxia (five of 21) to that in those dying of trauma (five of 20). It was present in two of 15 of those that died at once, and 13 of 35 of those who survived for varying periods with or without cardiopulmonary resuscitation. Myocardial contraction band necrosis was more common than diaphragmatic contraction band necrosis, being present in five of 11 of those who died at once, and 16 of 26 of those that survived for a period. Among individual subjects, the authors found no correlation of the presence of the diaphragmatic lesion with either cause or mode of death. Based on a comparison with the morphologically similar myocardial lesion, the etiopathogenesis of diaphragmatic contraction band necrosis may concern a local catecholamine effect.

Bone marrow involvement and obstructive jaundice in Farber lipogranulomatosis: clinical and autopsy report of a new case.

We report a case of Farber lipogranulomatosis in a girl with hepatosplenomegaly, macular cherry-red spot, and subcutaneous nodules who developed liver dysfunction with jaundice and ascites, and myelophthisic anaemia because of infiltration of bone marrow with storage cells. Acid ceramidase assay confirmed the diagnosis. We conclude that the bone marrow dysfunction and cherry-red spot are features of type IV Farber lipogranulomatosis that have not been previously recognized, and should be added to the clinical phenotypic description.

Terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27-->qter)].

We report on a terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27-->qter)] in a female newborn infant who died 45 hours after delivery and had multiple congenital abnormalities including bilateral anophthalmia, congenital heart disease, and abnormal genitalia. The findings are compared to those of four previously reported cases with terminal del (3q).