Familial variant of maxillonasal dysplasia?

A rare syndrome comprising midfacial hypoplasia, lack of anterior nasal spine, and malocclusion is described. To the best of our knowledge, only sporadic cases with a similar cluster of defects have been reported, usually with the appellation of Binder syndrome. We describe an affected mother and daughter, thus suggesting a dominant mode of inheritance.     

Haemorrhagic disease of the newborn in the British Isles: two year prospective study.

OBJECTIVE--To determine the incidence of haemorrhagic disease of the newborn in the British Isles, study risk factors, and examine the effect of vitamin K prophylaxis. DESIGN--Prospective survey of all possible cases of haemorrhagic disease of the newborn as reported by consultant paediatricians using the monthly notification cards of the British Paediatric Surveillance Unit and a follow up questionnaire for each case to validate the diagnosis and accrue further data. SETTING--Britain (England, Scotland, and Wales) and Ireland (Northern Ireland and the Irish Republic) during December 1987 to March 1990. PATIENTS--27 infants classified as having confirmed (n = 25) or probable (n = 2) haemorrhagic disease of the newborn. RESULTS--24 of the 27 infants were solely breast fed. 10 suffered intracranial haemorrhage; two of these died and there was clinical concern about the remainder. 20 infants had received no vitamin K prophylaxis, and seven had received oral prophylaxis. Relative risk ratios for these groups compared with babies who had received intramuscular vitamin K were 81:1 and 13:1 respectively. Six infants had hepatitis (alpha 1 antitrypsin deficiency in four), unsuspected until presentation with haemorrhagic disease of the newborn, of whom four had received oral prophylaxis. One other baby had prolonged jaundice. One mother had taken phenytoin during pregnancy. CONCLUSIONS--All newborn infants should receive vitamin K prophylaxis. Intramuscular vitamin K is more effective than oral prophylactic regimens currently used in the British Isles.     

Genetic patterns of transcobalamin II and the relationships with congenital defects

The vitamin B12-binding protein, transcobalamin II, is a trace component of plasma with a rapid turnover. This protein is essential for absorption, transport, cellular uptake and for recycling of vitamin B12 (cobalamin). Congenital transcobalamin II deficiency, an inborn error of metabolism is inherited as a recessive trait. The homozygous form of the deficiency is accompanied by severe clinical, hematological and immunological disturbances in the first months of life. Analytical, genetic, biochemical and clinical aspects of transcobalamin II in man and in vertebrates have been reviewed here. A genetic polymorphism for the protein has been found in man, rabbits and mice. Family studies revealed that the genetic patterns in man are determined by four polymorphic and several rare alleles. This genetic variability has been applied in paternity testing and in population studies. Transcobalamin II typing in families of patients with the inherited functional deficiency has led to identification of various deficient alleles in heterozygous carriers of the defects. Applying transcobalamin II typing after bone marrow transplantation demonstrated that this protein originates partly in the bone marrow. Subsequent investigations in cell culture have shown that human skin fibroblasts and cultured bone marrow synthesize and secret isotypes of a transport protein corresponding to the genetic isotypes observed in plasma. Comparison of transcobalamin II types in umbilical cord serum with the maternal types, has proven that the transcobalamin II activity in the cord serum is derived from the fetus. This finding will be of crucial importance in the early diagnosis of the deficiency syndrome.     

A deficiency of vitamin B6 is a plausible molecular basis of the retinopathy of patients with diabetes mellitus

Eighteen patients with diabetes mellitus, some of whom had variously retinopathy, pregnancy, and the carpal tunnel syndrome, and were variously treated with steroids and vitamin B6, have been overviewed for periods of 8 months to 28 years. We have established an association of a deficiency of vitamin B6 with diabetes by monitoring the specific activity of the erythrocyte glutamic oxaloacetic transaminase and again by the association with the carpal tunnel syndrome (C.T.S.). It has been known for a decade that C.T.S. is caused by a B6 deficiency. The absence of retinopathy in vitamin B6-treated diabetic patients over periods of 8 months - 28 years appears monumental. These observations are like discovery and constitute a basis for a new protocol to establish the apparent relationship of a deficiency of vitamin B6 as a molecular cause of diabetic neuropathy. Blindness and vision are so important that the strength or weakness of the observations are not important; the conduct of a new protocol is important.     

Pre-implantation diagnosis

The access to human pre-implantation embryos that is afforded by procedures now developed for the treatment of infertility presents the possibility of very early prenatal diagnosis, before implantation in the uterus, of certain genetic diseases. Only the normal embryos would be replaced in the mother for initiation of implantation and pregnancy. Early experiments on a mouse model for Lesch-Nyhan syndrome (HPRT-deficiency) show that pre-implantation diagnosis of genetic disease is feasible.     

A nutritional model of late embryonic vitamin A deficiency produces defects in organogenesis at a high penetrance and reveals new roles for the vitamin in skeletal development

Vitamin A plays an essential role in vertebrate embryogenesis. In the present study, pregnant vitamin A-deficient (VAD) rats were maintained during early pregnancy on the short half-life vitamin A metabolite, all-trans retinoic acid (atRA), in an amount sufficient to support normal development to E10.5, with a higher level of atRA (250 μg atRA/g diet) provided from embryonic day (E) 8.5-10.5 to prevent mid-gestational resorption. When limiting amounts of atRA (1.5 or 12 μg/g diet) were provided after E10.5, a highly reproducible and penetrant state of late fetal vitamin A deficiency (late VAD) was induced in the organs of developing fetuses. In addition, late VAD fetuses displayed both anteriorization of cervical regions and novel posteriorization events at the thoracic and sacral levels of the skeleton, and showed sternal and pelvic malformations not previously observed in early VAD or genetic models. The expression of several Hox genes (Hoxd3 and Hoxb4) was altered in late VAD embryos, with a reduction in Hoxd3 noted as early as 1 day after instituting deficiency. All late VAD-induced malformations were prevented by the addition of retinol starting at E10.5, whereas provision of a high level of atRA throughout pregnancy improved but could not completely rescue the development of all organ systems. This work defines a nutritional model in which vitamin A deficiency can be induced during fetal development, and reveals new functions for the vitamin in the development of the axial and appendicular skeleton.     

High prevalence of vitamin d deficiency in pregnant women: a national cross-sectional survey

An increasing number of studies suggest that vitamin D deficiency during pregnancy is associated with multiple adverse health outcomes in mothers, neonates and children. There are no representative country data available on vitamin D status of pregnant women in Europe. The aim of this study was to estimate the prevalence of vitamin D deficiency among Belgian pregnant women and to assess the determinants of vitamin D status in the first and third trimester of pregnancy. The women were selected via a multi-stage proportionate-to-size sampling design. Blood samples were collected and a questionnaire was completed face-to-face. 55 obstetric clinics were randomly selected and 1311 pregnant women participated in the study. The median serum 25-hydroxyvitamin D [25-(OH)D] concentration was significantly lower in the first trimester (20.4 ng/ml) than in third trimester (22.7 ng/ml). Of all women, 74.1% (95%CI = 71.8–76.5%) were vitamin D insufficient (25-(OH)D <30 ng/ml), 44.6% (95%CI = 41.9–47.3%) were vitamin D deficient (25-(OH)D <20 ng/ml), while 12.1% (95%CI = 10.3–13.8%) were severely vitamin D deficient (25-(OH)D <10 ng/ml). Of all women included, 62.0% reported taking vitamin D-containing multivitamins, of which only 24.2% started taking those before pregnancy. The risk of vitamin D deficiency (25-(OH)D <20 ng/ml) was significantly higher for less educated women and women who reported not going on holidays to sunny climates. The risk of severe vitamin D deficiency (25-(OH)D <10 ng/ml) decreased for women who reported alcohol consumption during pregnancy, decreased with more frequent use of sunscreen lotion and increased for smokers and women who reported preference for shadow. In conclusion, vitamin D deficiency is highly prevalent among pregnant women in Belgium and this raises concerns about the health consequences for the mother and the offspring. A targeted screening strategy to detect and treat women at high risk of severe vitamin D deficiency is needed in Belgium and in Europe.     

Microchimerism: incidental byproduct of pregnancy or active participant in human health?

It is now well recognized that cells traffic in both directions between fetus and mother during pregnancy. Moreover, fetal cells have been found to persist for years, probably for a lifetime, in the circulation of healthy women. Harboring of cells from another individual at low levels is called microchimerism. Women have a predilection to autoimmune disease, and chronic graft-versus-host disease, a condition of human chimerism, shares similarities with some autoimmune diseases. The specific HLA genes of donor and host are known to be of central importance in graft-versus-host disease, and HLA class II genes are important in autoimmune disease. Considered together, these observations led to the hypothesis that microchimerism and HLA genes of host and non-host cells are involved in autoimmune diseases. Alternative sources of microchimerism include transfer from a twin or the mother during pregnancy, or from blood transfusion. Studies of systemic sclerosis, primary biliary cirrhosis, Sj?grens syndrome, pruritic eruption of pregnancy, myositis, and thyroid disease have both lent support and raised doubts about a potential role of microchimerism in autoimmune disease.     

Molecular genetics of preeclampsia and HELLP syndrome — A review

Preeclampsia is characterised by new onset hypertension and proteinuria and is a major obstetrical problem for both mother and foetus. Haemolysis elevated liver enzymes and low platelets (HELLP) syndrome is an obstetrical emergency and most cases occur in the presence of preeclampsia. Preeclampsia and HELLP are complicated syndromes with a wide variety in severity of clinical symptoms and gestational age at onset. The pathophysiology depends not only on periconceptional conditions and the foetal and placental genotype, but also on the capability of the maternal system to deal with pregnancy. Genetically, preeclampsia is a complex disorder and despite numerous efforts no clear mode of inheritance has been established. A minor fraction of HELLP cases is caused by foetal homozygous LCHAD deficiency, but for most cases the genetic background has not been elucidated yet. At least 178 genes have been described in relation to preeclampsia or HELLP syndrome. Confined placental mosaicism (CPM) is documented to cause early onset preeclampsia in some cases; the overall contribution of CPM to the occurrence of preeclampsia has not been adequately investigated yet. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.     

Chronic Cholangitides: Aetiology,Diagnosis, and Treatment

A number of different chronic diseases affect the intrahepatic bile radicles or cholangioles. They include primary and secondary sclerosing cholangitis, primary biliary cirrhosis, chronic cholestatic drug jaundice, atresia, and carcinoma. Aetiological factors include infection, immunological changes, hormones, and congenital defects.Patients with chronic cholestasis have decreased bile salts in the intestinal contents and suffer from a bile salt deficiency syndrome. Failure to absorb dietary fat is managed by a low-fat diet and by medium-chain trigly-cerides which are absorbed in the absence of intestinal bile salts. Fat-soluble vitamin deficiencies are prevented by parenteral vitamins A, D, and K₁. Calcium absorption is defective, and improvement may follow intramuscular vitamin D, medium-chain triglycerides, a low-fat diet, and oral calcium supplements.In partial intestinal bile salt deficiency the anionic bile-salt-chelating resin cholestyramine controls pruritus though steatorrhoea increases. Pruritus associated with total lack of intestinal bile salts is managed by methyl-testosterone or norethandrolone, though the jaundice increases.     

Vitamin D and maternal and child health: Overview and implications for dietary requirements

The essentiality of vitamin D for normal growth and development has been recognized for over 80 years, and vitamin D fortification programs have been in place in the United States for more than 70 years. Despite the above, vitamin D deficiency continues to be a common finding in certain population groups. Vitamin D deficiency has been suggested as a potential risk factor for the development of preeclampsia, and vitamin D deficiency during infancy and early childhood is associated with an increased risk for numerous skeletal disorders, as well as immunological and vascular abnormalities. Vitamin D deficiency can occur through multiple mechanisms including the consumption of diets low in this vitamin and inadequate exposure to environmental ultraviolet B rays. The potential value of vitamin D supplementation in high‐risk pregnancies and during infancy and early childhood is discussed. Currently, there is vigorous debate concerning what constitutes appropriate vitamin D intakes during early development as exemplified by differing recommendations from the Institute of Medicine Dietary Reference Intake report and recent recommendations by the Endocrine Society. As is discussed, a major issue that needs to be resolved is what key biological endpoint should be used when making vitamin D recommendations for the pregnant woman and her offspring. Birth Defects Research (Part C) 99:24–44, 2013. © 2013 Wiley Periodicals, Inc.     

Vitamins and brain development.

Effects of deficiency of vitamins on early development of brain have been reviewed. Unusual developmental problems in neurogenesis specific for the brain and impairment of its functional capacities due to vitamin deficiency have been discussed. The species-specific "critical periods" in development of various systems have been mentioned. Indices such as reflex activity, locomotion, special senses, cognition and adaptive behavior were used for assessing brain maturation in experimental models and humans. Significant examples include brain anomalies in humans and other mammals caused by retinoid excess or deficit; increase in calbindin D28K, a vitamin D dependent calcium-binding protein during postnatal period in rat; hydrocephalus and exencephaly in prenatal rats and subarachnoidal or intracerebral hemorrhage in infants caused by vitamin E deficiency. Peripheral neuropathic lesions leading to infantile beriberi is caused by thiamine deficiency. Impaired growth in retinal layers leading to delay in maturation of electroretinogram and depth-perception in postnatal rats occur due to pyridoxine deficiency. Infants of severely vitamin B12 deficient mothers show abnormalities in behavior involving basal ganglia and pyramidal tract. Folic acid deficiency results in delayed maturation of the basic electroencepalographic patterns. In addition, vitamin-interactions leading to developmental errors have been pointed out. Vitamin B6 deficiency impairs vitamin B12 absorption and biotin deficiency may be aggravated by pantothenic acid deficiency. Vitamin C deficiency resulting in impaired metabolism may produce symptoms of deficiency of folic acid. Another characteristic examples is that iron absorption from dietary sources is dependent on ascorbic acid.     

Vitamin E sensitive genes in the developing rat fetal brain: a high-density oligonucleotide microarray analysis

Vitamin E (tocopherols and tocotrienols) is essential for normal neurological function. Recently we have reported that the neuroprotective properties of tocotrienols are much more potent than that of the widely studied tocopherols (Sen, C.K., Khanna, S., Roy, S. and Parker, L. (2000) J. Biol. Chem. 275, 13049–13055). The objective of this study was to evaluate whether (i) oral supplementation of tocotrienols during pregnancy is bioavailable to fetal and mother brains; (ii) short-term change in dietary vitamin E levels of pregnant rats influences gene expression profile of developing fetal brains. We report that dietary tocotrienol is bioavailable to both mother and fetal brains. The enrichment is more in fetal brain tissue. Using a GeneChip microarray expression profiling approach we have identified a specific set of vitamin E sensitive genes in the developing rat fetal brain.     

Genotyping and prenatal assessment of collagen lysyl hydroxylase deficiency in a family with Ehlers-Danlos syndrome type VI.

Collagen lysyl and prolyl hydroxylase activities were measured in cultured fibroblasts from a child with clinical features of Ehlers-Danlos syndrome. Lysyl-to-prolyl hydroxylase activity ratios in cells from the proband, mother, father, and control were .24, .86, .52, and 1.00, respectively, providing a biochemical diagnosis of Ehlers-Danlos syndrome type VI and indicating an autosomal recessive mode of inheritance in this family. Prenatal assessment of lysyl hydroxylase deficiency was requested and accomplished for the first time during a subsequent pregnancy in the family. A series of control cultures established lysyl hydroxylase activity to be similar in cultured amniotic fluid cells (AF and F cells) and in cultured dermal fibroblasts. Cultured F and AF cells from the monitored pregnancy had enzyme activity similar to controls, indicating that the fetus should not be affected by lysyl hydroxylase deficiency. This finding was confirmed by demonstration of normal lysyl hydroxylase activity in fibroblasts cultured from the newborn baby. These studies show that cells cultured from second trimester amniotic fluid have collagen lysyl hydroxylase activity similar to that in dermal fibroblasts, making prenatal diagnosis of lysyl hydroxylase deficiency possible.     

Effect of vitamin D deficiency on skeletal development during early growth in the rat

To define the role of vitamin D in early development, female weanling rats were grown to maturity on a vitamin D-deficient diet and mated with normal males. At Day 20 of pregnancy the weight and total body calcium of fetuses were determined. At various times after parturition, pups were sacrificed. Plasma samples were analyzed for calcium and phorphorus, and femurs were characterized as to volume, dry weight, ash weight, and total calcium. The results indicate that vitamin D deficiency with its accompanying hypocalcemia does not impair placental transfer of calcium nor weight gain of the fetus. Vitamin D deficiency does appear to increase calcium accumulation in the fetus. After parturition vitamin D is functional in maintaining a normocalcemia as early as 3 days postpartum and its importance increases with age of the neonate. Bone mineralization is clearly disrupted by Day 14 as judged by calcium content per unit bone volume and the severity of the defect increases with age. Both vitamin D and normal concentrations of calcium and phosphorus appear to be essential for proper skeletal development during early growth postpartum.     

Vitamin A treatment for night blindness in primary biliary cirrhosis.

Three patients with late stage primary biliary cirrhosis were found to have appreciable night blindness. Serum vitamin A concentrations were low in all three patients despite regular intramuscular supplementation in two. All patients responded dramatically to high dose oral supplementation, with full recovery of adaptation to dark and visual fields. Oral rather than intramuscular vitamin A supplementation seems appropriate in the prevention of ocular complications of vitamin A deficiency in biliary cirrhosis.     

Probable case of Binder syndrome in a skeleton from Quarai,New Mexico

Binder syndrome (maxillonasal dysplasia) is a not uncommon disorder reported in the clinical literature and is characterized by hypoplastic development of the midface. An extensive review of the paleopathology literature did not reveal any examples of Binder syndrome. In this paper, a probable case of Binder syndrome in a female skeleton, 16-17 years at age of death, from Quarai, New Mexico (ca. AD 1375-1450) is presented. This case was identified during standard documentation prior to repatriation at the National Museum of Natural History, Smithsonian Institution.The skull of this individual (381243) exhibits unusual facial features, including an underdeveloped midface, flattened glabella, absent nasal spine, and apparent alveolar prognathism, in addition to a vertebral anomaly. All of these characteristics are consistent with skeletal dysmorphologies associated with Binder syndrome. Measurements of the Quarai skull are compared with published data on Binder patients and normal control groups in order to quantify the nature of the observed morphology. Univariate analysis of craniometric/cephalometric data provides further support for a diagnosis of Binder syndrome, as critical measurements on the Quarai skull are consistent with those reported in Binder patients and significantly different from those reported for normal control groups. In addition to presenting a probable prehistoric case of Binder syndrome, this paper demonstrates the applicability of using direct comparisons of clinical data to help identify unusual conditions in skeletal remains.     

Partial androgen receptor deficiency and mixed gonadal dysgenesis in Drash syndrome

Summary Drash syndrome associates a nephropathy characterized by a diffuse mesangial sclerosis of early onset, Wilms tumor, and male pseudohermaphroditism (MPH). A patient with Drash syndrome is reported with the following: karyotype 46,XY, external genitalia near normal female, mixed gonadal dysgenesis, severe androgen receptor deficiency demonstrated for the first time in this syndrome. The possibility of a common genetic denominator with the del 11p13 WAGR complex is suggested. MPH/nephroblastoma association is common. Androgen receptor deficiency has been observed in one case of each syndrome, respectively.     

Familial Down's syndrome.

A family is reported in which the same mother conceived two children with trisomy 21. The pregnancy with the second affected child was interrupted after diagnostic amniocentesis. Maternal chromosome analysis was normal. This family and those previously reported suggest that there is an increased recurrence risk of trisomy 21 after the birth of an affected individual, possibly caused by a genetic tendency for non-disjunction. After the birth of a child with Down's syndrome, amniocentesis and chromosome analysis of cultured amniotic fluid cells is indicated in each further pregnancy, irrespective of maternal age.