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A 13-yr-old girl with dyskeratosis congenita is presented. Besides oral leukoplakia and nail dystrophies, there was evidence of pancytopenia, growth retardation, alopecia, mental retardation and microcephaly. The oral findings included caries, gingival recession, short-blunted roots, gingival bleeding, tooth mobility and severe alveolar bone loss resembling juvenile periodontitis.
Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain-behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1(-/-) mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain-behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role.
Two children are described with congenital abnormalities (microcephaly, nystagmus, deafness, hepatomegaly) and the anomalous feature of triglyceride deposits in peripheral adipose tissue associated with severe malnutrition. Peripheral adipose tissue of one of these children displayed: (a) reduced sensitivity of adenyl cyclase to stimulation by noradrenaline (b) no response in tissue levels of cyclic AMP when stimulated by isoprenaline and (c) impaired release of glycerol following stimulation with isoprenaline. The other child, with similar clinical features, showed abnormal deposits of glycogen in the liver. It is postulated that a primary metabolic defect occurs in peripheral adipose tissue (and possibly at other sites such as the liver) that interferes with triglyceride (and glycogen) mobilization during prolonged malnutrition.
A 14-month-old female with the Coffin-Siris syndrome is described. Typical features included underweight at birth, growth retardation, microcephaly, profound mental retardation, severe hypotonia with lax joints, feeding difficulties and frequent respiratory tract infections; sparce scalp hair, small nose, epicanthic folds, a prominent philtrum and full lips; a congenital heart defect; hypoplasia or aplasia of the distal phalanges of digits 2--5 and the corresponding nails, especially of the fifth fingers and toes, and aplasia of the middle phalanges of the little fingers and the second and fifth toes; severe delay in bone maturation. The proposita also showed hypoplasia of the lateral portions of both clavicles. Inheritance of the Coffin-Siris syndrome is possibly autosomal recessive.
A 10-year-old boy with microcephaly, stunted growth, mental retardation, café-au-lait spots and immunodeficiency is described. An older brother of the patient had the same clinical symptoms and a more severe immunodeficiency. Cytogenetic studies in the proband revealed a typical form of chromosome instability with multiple rearrangements of chromosomes 7 and 14. Such abnormalities were also present, though in very low frequencies, in the father and three of the phenotypically normal sibs. The similarity of the symptoms in the two sibs, the close consanguinity of their parents and the results of the cytogenetic studies in the family favour the hypothesis that the disorder is an inherited one. The clinical features and the chromosome aberrations as present in the proband are usually found in chromosomal breakage syndromes, but it was possible to exclude each of the classical chromosomal breakage syndromes on clinical and/or cytogenetic grounds.
A boy presented with ectrodactyly (lobster claw deformity), bilateral cleft lip and palate, semilobar holoprosencephaly and microcephaly, associated with congenital hypogonadotropic hypogonadism and central diabetes insipidus. Other aspects of pituitary function were normal. We suggest that the ectrodactyly-ectodermal dysplasia-clefting syndrome can be associated with a variety of hypothalamo-pituitary dysfunctions, in addition to the already described isolated growth hormone deficiency.
MPKU pregnancies, with or without dietary treatment to reduce maternal plasma phenylalanine (phe), show variable, increased non-physiologic levels, as the putative cause of fetal teratogenicity. Cerebral dysgenesis with clinical neonatal microcephaly and congenital heart disease indicates altered organ morphogenesis. Although there is not an established precise relationship between maternal phe levels and outcome, dietary restriction before or early in gestation is universally advised. Both human experience and animal research have suggested differential organ responses to high and low phe levels. Structural microencephaly may be due to reduced brain volume or abnormal regional brain development. Infants in MPKU are also at risk to develop PKU. Microencephaly was evident by MRI in 8 of 21 infants born to 12 MPKU mothers; 2 infants of one mother developed PKU. All levels of gestational plasma phe were associated with otherwise structurally normal infant microencephalic brains appropriate for age in myelination. CHD occurred in one microencephalic infant of a classic MPKU treated in the first trimester. Maternal, cord and neonatal plasma phenylalanine at delivery did not correlate with teratogenic effects. Only untreated 'classic' MPKU fetal effects appear predictable.
The impact of intrauterine growth restriction (IUGR) in very low birthweight preterm infants weighing < or = 1250 g was determined by comparing longitudinal growth and neurodevelopmental outcome to an adjusted age of 36 months in 52 intrauterine growth restricted children, with 55 birthweight-matched and 56 gestational age-matched children. None of these children had chromosomal anomalies, congenital infections, or major congenital malformations. Gestational ages of intrauterine growth restricted, birthweight- and gestational age-matched infants were 30 (+/-3), 26 (+/-2), 29 (+/-2) weeks: birthweights were 842 (+/-232), 872 (+/-201) and 1094 (+/-142) g, respectively. Intrauterine growth restricted children had fewer complications during initial hospitalization (p < 0.05), and had lower weights and head circumferences at follow-up (p < 0.05). No significant differences were present in major neurodevelopmental disabilities between the intrauterine growth restricted and two comparison groups. Persistence of microcephaly was associated with adverse neurodevelopmental outcome.
Endocast analysis of the brain Homo floresiensis by Falk et al. (Reports, 8 April 2005, p. 242) implies that the hominid is an insular dwarf derived from H. erectus, but its tiny cranial capacity cannot result from normal dwarfing. Consideration of more appropriate microcephalic syndromes and specimens supports the hypothesis of modern human microcephaly.
A case of ring D13 chromosome, confirmed by trypsin banding, is described. Reviewing 21 cases from published reports, the most common features of this syndrome are microcephaly and associated mental retardation, poor uterine growth, deformed auricles, hypertelorism, epicanthus, broad nasal bridge, and genital defects in males.
We report a child with multiple malformations caused by trisomy for the distal part of the long arm of chromosome No 5. A neonatal diagnosis of Down's syndrome had previously been made on the basis of clinical examination and the detection of an additional chromosome not unlike No 21. A subsequent clinical re-evaluation, with the cooperation of the parents who permitted further studies, led to the confirmation of the true diagnosis. The mother was the carrier of a balanced translocation between chromosome No 5 and No 14. The child had severe growth and psychomotor retardation and characteristic features: microcephaly, antimongoloid slant, epicanthus, low set ears, down-turned mouth, and long upper lip. She was hypertonic and a congenital heart disease (atrial septal defect) was present. We have compared this case with others known to be trisomic for segment 5q31-qter.
Serine concentrations were markedly decreased in the cerebrospinal fluid of two brothers with congenital microcephaly, profound psychomotor retardation, hypertonia, epilepsy, growth retardation, and hypogonadism. The youngest boy also had congenital bilateral cataract. Magnetic resonance imaging of the brain showed evidence of dysmyelination. Plasma serine as well as plasma and cerebrospinal fluid glycine concentrations were also decreased but to a lesser extent. Treatment with oral serine in the youngest patient significantly increased cerebrospinal fluid serine and abolished the convulsions. In fibroblasts of both patients, a decreased activity was demonstrated of 3-phosphoglycerate dehydrogenase, the first step of serine biosynthesis (22% and 13% of the mean control value). This is an unusual disorder as the great majority of aminoacidopathies are catabolic defects. It is a severe but potentially treatable inborn error of metabolism that has not been previously reported in man.
BACKGROUND: Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder. NBS-1, the gene defective in NBS, is located on chromosome 8q21 and has recently been cloned. The gene product, nibrin, is a novel protein, which is member of the hMre11/hRad50 protein complex, suggesting that the gene is involved in DNA double strand break repair. AIMS: To study the clinical and laboratory features of NBS as well as the genotype-phenotype relation. METHODS: Fifty five patients with NBS, included in the NBS registry in Nijmegen were evaluated. The majority of the patients were of eastern European ancestry. Most of them had shown a truncating 5 bp deletion 657-661 delACAAA. Four further truncating mutations have been identified in patients with other distinct haplotypes. RESULTS AND CONCLUSIONS: Essential features found in NBS were microcephaly, usually without severe retardation, typical facial appearance, immunodeficiency, chromosomal instability, x ray hypersensitivity, and predisposition to malignancy. In 40% of the patients cancer was noted before the age of 21 years. Important additional features were skin abnormalities, particularly café au lait spots and vitiligo, and congenital malformations, particularly clinodactyly and syndactyly. Congenital malformations, immunodeficiency, radiation hypersensitivity, and cancer predisposition were comprehensible in case of dysfunctioning of DNA repair mechanisms. No specific genotype-phenotype relation could be found. Patients with the same genotype may show different phenotypes and patients with different genotypes may express the same phenotype. Specific mutations did not lead to specific clinical features.
A newborn male infant, whose karyotype was 46,XY,del(10)(p13) is presented. The clinical features included cleft lip and palate, preauricular pits, low set malpositioned auricles, antimongoloid slant of the eyes, microcephaly, micrognathia, congenital heart disease, hypertrophic pyloric stenosis, cryptorchidism, and abnormal dermatoglyphics. The child died at the age of 3 months in overwhelming urinary infection with septicemic complications. It is suggested that the features described here may represent a new, clinically recognizable chromosomal syndrome.
Scalp hair patterns have been examined in 1901 healthy subjects and 1789 severely subnormal patients. Patients with Down's syndrome had a highly significant excess of midline occipital whorls and a deficit of right-sided occipital whorls. Five out of 44 patients with microcephaly had a distinct 'up-sweep' of the frontal hair, a much lower proportion than found previously. Patients with unspecified mental subnormality had a highly significant deficit of multiple occipital whorls. Cutis verticis gyrata was noted incidentally in 15 subnormal patients, 13 of whom were males. Observation of hair patterns in individual patients with mental subnormality is of theoretical interest but is unlikely to be of great practical value.
We have identified a partial deletion of the long arm of chromosome 7 in a newborn baby boy. His major anomalies were microcephaly, synbrachydactyly, diastisis recti, hypospadias, short neck, and widely spaced nipples.
This paper describes 6 individuals, occurring in 3 generations of a single family, who were affected by a distinct syndrome which included: retardation and microcephaly; a small oval face with almond-shaped eyes, droopy eyelids, a small nose, and small downturned mouth; minor acral skeletal anomalies, and short stature. Craniosynostosis, heart defects, and limited elbow extension were seen less frequently. Expression was variable and parents who were in the direct vertical line of transmission of the syndrome showed few, if any, overt signs of the disease. However, the metacarpal/phalangeal profile of the parents showed a similar pattern to that seen in the affected individuals, and it is suggested that this profile may be the most sensitive indicator of carrier status.
A Pakistani couple, who were first cousins once removed through their fathers, and whose mothers were also related, had two liveborn children, a boy and a girl. Both children died within 2 hours of birth with occipital encephalocele, microcephaly, polycystic kidneys, and cystic distension of intrahepatic bile ducts. Both children had normal karyotypes. These abnormalities constitute Meckel's syndrome (dysencephalia splanchno-cystica); this is the fifth report of parental consanguinity, adding further support to the evidence for autosomal recessive inheritance of the disorder.