"Vascular neurofibromatosis" and infantile gangrene.

An 11-year-old boy with slowly progressive gangrene caused by vasculopathy similar to that of neurofibromatosis (NF) type 1 (NF I; von Recklinghausen disease [NFvR]) and a newborn girl with idiopathic gangrene with vascular changes resembling those of NFvR prompted the analysis of all 105 propositi with NF (NF I and NF II) evaluated between January 2, 1982, and December 31, 1986, at the genetics clinic of University of South Florida. They were analyzed for renal hypertension, symptomatic ischemia, and known vascular changes. One additional 27-month-old boy with NFvR was found to have extensive vascular changes with renal hypertension. The vasculopathy indicated asymmetric over/undergrowth of cellular and extracellular components of the vascular wall and implied dysregulation of the paracrine growth mechanism. Immunocytochemical studies of affected vessels were done only in the 11-year-old boy and showed positive neuron-specific enolase, S-100 protein, and glial fibrillary acidic protein (GFAP) reactions indicative of Schwann cell involvement. The vascular changes in children with NFvR are mostly asymptomatic; however hypertension secondary to renal artery stenosis and/or Moya-moya disease have been reported infrequently. Our patients with vasculopathies provoked thoughts in regard to the so-called vascular NF, its place in current NF nomenclature and classification, relationship to fibromuscular dysplasia (FMD), and possible role in infantile gangrene.

Polyasplenia complex with mesocardia and renal agenesis in an infant of a diabetic mother.

Despite improved prenatal care, infants of diabetic mothers (IDM) have an increased risk of congenital malformations. We report on an IDM with multiple congenital anomalies consistent with the polyasplenia complex with associated mesocardia and renal agenesis. The morphologic characteristics of these malformations are discussed. Special emphasis is given to the polyasplenia complex as an example of midline developmental field defect. The importance of maternal levels of hemoglobin A1c in relation to congenital malformations is addressed.

Golgi-Kopsch silver study of the brain of a patient with untreated phenylketonuria, seizures, and cortical blindness.

This report describes the morphological changes observed in the brain of an untreated 27-year-old man with phenylketonuria, cortical blindness, and seizures. Golgi-Kopsch silver, cresyl violet, and hematoxylin and eosin stains were used to study cell structure and organization of the cerebellum, the lateral geniculate nuclei, the visual cortex, frontal cortex, and hippocampus. Extensive neuronal losses occurred in the right lateral geniculate nucleus (LGN), the visual cortex, and hippocampus. The left LGN, cerebellum, and frontal cortex retained neuronal components; there was a reduction in the number of dendritic processes on the Purkinje cells of the PKU subject. The loss of neurons in the LGN and occipital cortex is related to the blindness and the neuronal loss in the hippocampus is related to seizure activity.

Megacystis-microcolon-intestinal hypoperistalsis syndrome and aganglionosis in trisomy 18.

Ultrasonography at 23 weeks of gestation documented the presence of megacystis with horseshoe kidney, microcolon, intestinal malrotation, and decreased amniotic fluid volume. After pregnancy termination, an autopsy was performed. The external phenotype was diagnostic of the trisomy 18 syndrome confirmed by chromosome examination. The fetus also had a massively distended bladder with parchment-thin wall, microcolon, intestinal malrotation but no urethral obstruction or hydronephrosis. No ganglion cells were present in the colon or bladder. This has not been mentioned in other reported cases and, therefore, suggests pathogenic heterogeneity. The megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare autosomal recessive condition of unknown pathogenesis whose genes map to 15q24. Thus, its previously undescribed presence in trisomy 18 further suggests etiologic heterogeneity.

Complete absence or deficiency of one half of the body.

Here we report on an apparently unprecedented case of virtually complete absence of the left half of the body, with resulting severe deformity of the right half. The fetus was stillborn with polyhydramnios at 31 1/2 weeks of gestational age. A second patient may be a mild example of this extraordinary phenomenon with deficiency of organs, predominantly on the left side. The nosology and developmental implications are discussed briefly.

Increased expression of low-density lipoprotein receptors in a Smith-Lemli-Opitz infant with elevated bilirubin levels.

We report on an infant girl with severe RSH or Smith-Lemli-Opitz syndrome with hyperbilirubinemia. The infant died at age 2 months. Sterol analysis of liver and brain tissues showed marked elevations of 7-dehydrocholesterol with decreased levels of cholesterol. Immunocytochemical analysis demonstrated remarkable increases in low-density lipoprotein (LDL) receptors in these tissues, indicative of a deficiency in available cholesterol for tissue needs.

Bronchopulmonary-foregut malformations: a continuum of paracrine hamartomas?

The bronchopulmonary-foregut malformations (BPFM) are usually sporadic, solitary cystic hamartomas involving conducting airways, arteries, venous drainage, and lung parenchyma. Transitional, compound hamartomas exist, and only their morphology is well-known. Between 1984-1994 we encountered and studied 10 unrelated patients and a stillborn infant with BPFM (out of 24,000 families). Ten were diagnosed in utero and one at birth as having congenital cystic adenomatoid malformation of the lung (CCAML). Postnatally, two diagnoses (20%) were corrected to bronchogenic cyst (BC) and diaphragmatic hernia, respectively. Bilateral lung involvement was present in 1 patient, and in 2 there was a considerable macroscopic regression of the hamartoma. Histologic studies of the six resected CCAML confirmed the diagnosis and implied dysregulated paracrine growth with its cellular and extracellular growth factors, protooncogenes, oncogenes, cytokines, cell-adhesive molecules, and receptors of these regulatory peptides, and their complex interactions as developmental morphogens in time and space.

Nail-patella syndrome in a spontaneously aborted 18-week fetus: ultrastructural and immunofluorescent study of the kidneys.

Nail-patella syndrome (NPS), hereditary onycho-osteodysplasia, is an autosomal dominant disorder of nail dystrophy, patellar absence or hypoplasia, incomplete elbow extension, conical posterior iliac horns, and nephropathy. We studied the kidneys of an 18-week spontaneously aborted fetus of a mother with the NPS. Ultrastructural examination of the kidney showed thickening of the capillary walls of the glomeruli and mesangium. There was irregular thickening of basement membranes with subendothelial fibrillar electron-dense deposits. Immunofluorescence showed fibrinogen deposition in glomerular basement membranes. Fibrinogen deposition in utero may ultimately lead to glomerular fibrosis and intrabasement membrane collagen deposition as seen in the adult renal lesion of this syndrome. This is the first report of the NPS in which the renal abnormalities have been studied in a fetus. These findings provide support for possible prenatal diagnosis of NPS by intra-uterine kidney biopsy.

Multiple meningiomas, craniofacial hyperostosis and retinal abnormalities in Proteus syndrome.

Because clinical evidence suggests that Proteus syndrome may be caused by a somatic mutation during early development, resulting in mosaicism, the possible types of abnormalities and their clinical distributions are highly variable. Here, we report on an unusual patient with Proteus syndrome. Manifestations included multiple meningiomas, polymicrogyria, and periventricular heterotopias. Both eyes had epibulbar cystic lesions. The retina showed diffuse disorganization with nodular gliosis, retinal pigmentary abnormalities, chronic papilledema, and optic atrophy. Other abnormalities included progressive cranial, mandibular, maxillary, and auditory canal hyperostoses, epidermal nevi, and mental deficiency. The limbs were proportionate, and the hands and feet were normal.

A 7-year old white-male boy with progressive neurological deterioration.

A 9-month-old boy presented with rapid deterioration of psychomotor development. He developed seizures at 2 months, and shortly thereafter lost motor skills and developed feeding difficulties, increased startle response, red maculas, and decreased vision. His measurements, including head circumference, were greater than the 95th centile. No organomegaly was found. Serum determination of the hemoxsaminidases confirmed the diagnosis of Sandhoff disease.

Ocular manifestations in Proteus syndrome.

We report on the ocular manifestations of a Proteus syndrome patient. Several of the manifestations are due to severe maldevelopment and malfunction of the neuroretina including strabismus, nystagmus, high myopia, and retinal pigmentary abnormalities. In reviewing the literature, strabismus and epibulbar tumors were recorded most commonly. Some articles about presumed Proteus syndrome are spurious; these have not been included here. Also, because of anecdotal and nonsystematic study of the eye and because of the ascertainment bias inherent in literature reports, numbers of cases of each ocular manifestation have not been tabulated.

Evidence for the "midline" hypothesis in associated defects of laterality formation and multiple midline anomalies.

A male infant was liveborn at 38 weeks of gestation to a G4P1AB2, 22-year-old, mother. Polyhydramnios and multiple congenital anomalies were noted by ultrasonography; the infant died 5 min after birth. At autopsy, the infant had multiple defects of blastogenesis including midline anomalies with asplenia and abnormalities of laterality formation. The laterality defects were unusual in that they combined asplenia with hypoplastic, symmetrically unilobate lungs and bilateral hyparterial bronchi more consistent with polysplenia, abdominal situs inversus with midline stomach, symmetric liver, and left gallbladder. No intracardiac abnormalities were present, but there was azygous continuation of the inferior vena cava. Additional multiple midline defects included bronchoesophageal fistula, duodenal atresia, absence of posterior leaf of diaphragm; horseshoe adrenal gland; microcephaly; Dandy-Walker anomaly with agenesis of cerebellar vermis and occipital encephalocele; holoprosencephaly with orbital encephalocele, midline defect of the orbital plate of the skull, bilateral anophthalmia, double proboscis with bilateral choanal atresia, midline upper lip and palatal cleft; single-lobed thyroid; hypoplastic external genitalia with midline cleft of scrotum, long tapering fingers, and defects of the cranium at the sites of orbital and occipital encephaloceles. Defects of laterality frequently are associated with other complex midline anomalies, which both result from a disturbance of pattern formation during blastogenesis, i.e., the induction of the progenitor fields. The latter are the result of the establishment of upstream expression domains of growth and transcription factors and other morphogens. Many of these and other genetic systems, expressed asymmetrically around the midline, are responsible for laterality formation and are the result of upstream and subsequent downstream gene expression cascades through the expression of genes such as HOX genes; bFGF; transforming growth factor beta/activins/BMP4; WNT-1,8; and SHH.

Spinocerebellar ataxia, hypogonadotropic hypogonadism, and choroidal dystrophy (Boucher-Neuhäuser syndrome)

We describe two families (including one previously reported) in which cerebellar or spinocerebellar ataxia, hypogonadotropic hypogonadism, and choroidal dystrophy result from abnormal function of an autosomal recessive gene. Review of the literature adds one other family with this disorder. These three examples confirm the existence of this traid as a specific, pleiotropic, single-gene syndrome. Careful ophthalmologic evaluation of patients with ataxia and hypogonadotropic hypogonadism may identify additional cases.

Polyphenotypic small-cell orbitocranial tumor.

A male infant was born with a massive orbitocranial tumor without evidence of metastasis. On light microscopy, the histologic pattern of the tumor was that of a largely necrotic and highly undifferentiated small round cell neoplasm of uncertain origin. Ultrastructural features of the primitive cells included a rare tight junction and myofibril. Immunohistochemical studies showed positive staining for cytokeratin, vimentin, muscle-specific actin, neuron-specific enolase, and S100 protein and negativity for desmin and leukocyte common antigen. We believe this case represents an example of a polyphenotypic small-cell tumor of childhood with epithelial, rhabdomyoblastic, and neuroectodermal differentiation.

Comparison of an isoelectric focusing technique and high-performance liquid chromatography for determination of fetal hemoglobin levels.

The authors previously have reported measurements of fetal hemoglobin in infants in blood samples taken at autopsy using an isoelectric focusing (IEF) procedure. The current study was undertaken to compare this methodology with a high-performance liquid chromatography (HPLC) procedure. The correlation coefficient between the IEF and HPLC procedures was 0.938. The HPLC method is technically easier and has fewer disadvantages than the IEF procedure and is recommended for the determination of fetal hemoglobin levels.

Smooth muscle cell depletion and collagen types in progeric arteries.

Review of two autopsy cases of progeria confirms severe smooth muscle cell (SMC) depletion in the atherosclerotic aortic media and the presence of collagen types I, III, IV, V, and VI in the aorta and renal vessels as is consistent with atherosclerotic disease.

Histological and ultrastructural features of atherosclerosis in progeria.

This histological and ultrastructural study of a limited amount of vascular tissue from a progeric woman of 20 years who died of traumatic subdural hemorrhage supports the belief that the vascular changes are atherosclerotic. The unusual features observed were collagen fibrils with a relatively small diameter in the atherosclerotic intima and media, extensive loss of mural smooth muscle cells particularly in the aorta, and widespread contraction bands in smooth muscle cells in vascular and nonvascular tissues. Smooth muscle cells appear to be unusually susceptible to hemodynamic and ischemic stress. Further autopsy studies are required to elucidate the etiology and pathogenesis of this unique disease.

Suspended rocking cradles, positional asphyxia, and sudden infant death.

OBJECTIVE: To describe the risk of unexpected death in infants who are placed in suspended rocking cardles. MAIN OUTCOME MEASURES: Ten cases of sudden infant death and 5 cases of infant asphyxia with successful resuscitation reported to the Consumer Product Safety Commission were analyzed. The death scene investigation reports and autopsy material were made available for evaluation. All 15 cases implicated a suspended head-to-toe rocking cradle. RESULTS: Infants were aged 3 months or younger and were found in the facedown prone position when discovered. The cradle was tilted at greater than 5 degrees, and the head was wedged at one end of the cradle. A locking pin was not used in 14 cases. Ten of the 15 infants died. The autopsy reports listed sudden infant death syndrome as the cause of death. CONCLUSIONS: Suspended rocking cradles represent a potentially lethal sleeping environment and should not be used without a locking pin in place. Infants should be placed in the supine position for sleep.

The fatty acid composition of maternal diet affects the response to excitotoxic neural injury in neonatal rat pups.

Fatty acids and their derivatives play a role in the response to neural injury. The effects of prenatal and postnatal dietary fatty acid composition on excitotoxic neural injury were investigated in neonatal rat pups. Dams were fed during gestation and lactation a diet whose fat source was either corn oil or menhaden fish oil. On postnatal day 3, litters were culled to 10 per dam. On postnatal day 4, excitotoxic neural injury was induced by infusion of the glutamate analog N-methyl-DL-aspartate (NMA) into the left cerebral hemisphere. Three days later, pups were killed and brains were removed for histological and volume assessments. Levels of arachidonic acid were 2.3-fold higher in cerebrums of pups in the corn oil group than in the fish oil group. Left cerebral hemispheres among all pups were atrophic. Right cerebral hemispheres of pups in the corn oil group showed more histological evidence of edema, and had significantly higher volumes than pups in the fish oil group (66 vs. 42 mm2, p=0.007). These data suggest that the fatty acid composition of prenatal and/or postnatal diet can affect the neonatal response to excitotoxic neural injury.

What lies ahead in infant nutrition.

Factors in human milk serve as stimuli for present and future investigation as supplements for infants. These substances involve macronutrients and micronutrients. Some substances such as minerals may serve as guidelines for minima and maxima for infant nutrition. While nutritional studies are needed for the prevention of disease, simultaneous nutritional studies for low birth weight and ill infants will bring major alterations in understanding of nutritional needs and types of feedings to become available.