An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

/pdf/homocysteine-and-cardiovascular-disease-1zad76k6jt.pdf

Homocysteine and Cardiovascular Disease

Rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continues to be reported in the United States. There are also concerns for vitamin D deficiency in older children and adolescents. Because there are limited natural dietary sources of vitamin D and adequate sunshine exposure for the cutaneous synthesis of vitamin D is not easily determined for a given individual and may increase the risk of skin cancer, the recommendations to ensure adequate vitamin D status have been revised to include all infants, including those who are exclusively breastfed and older children and adolescents. It is now recommended that all infants and children, including adolescents, have a minimum daily intake of 400 IU of vitamin D beginning soon after birth. The current recommendation replaces the previous recommendation of a minimum daily intake of 200 IU/day of vitamin D supplementation beginning in the first 2 months after birth and continuing through adolescence. These revised guidelines for vitamin D intake for healthy infants, children, and adolescents are based on evidence from new clinical trials and the historical precedence of safely giving 400 IU of vitamin D per day in the pediatric and adolescent population. New evidence supports a potential role for vitamin D in maintaining innate immunity and preventing diseases such as diabetes and cancer. The new data may eventually refine what constitutes vitamin D sufficiency or deficiency.

/pdf/prevention-of-rickets-and-vitamin-d-deficiency-in-infants-1v6ek4x7y2.pdf

Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents

Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

/pdf/hirschsprung-disease-associated-syndromes-and-genetics-a-1da3jmvt8r.pdf

Hirschsprung disease, associated syndromes and genetics: a review

Background Previous studies have suggested that hyperhomocysteinemia may be a risk factor for venous thrombosis. To assess the risk of venous thrombosis associated with hyperhomocysteinemia, we studied plasma homocysteine levels in patients with a first episode of deep-vein thrombosis and in normal control subjects. Methods We measured plasma homocysteine levels in 269 patients with a first, objectively diagnosed episode of deep-vein thrombosis and in 269 healthy controls matched to the patients according to age and sex. Hyperhomocysteinemia was defined as a plasma homocysteine level above the 95th percentile in the control group (18.5 μmol per liter). Results Of the 269 patients, 28 (10 percent) had plasma homocysteine levels above the 95th percentile for the controls, as compared with 13 of the controls (matched odds ratio, 2.5; 95 percent confidence interval, 1.2 to 5.2). The association between elevated homocysteine levels and venous thrombosis was stronger among women than among men and increased wit...

/pdf/hyperhomocysteinemia-as-a-risk-factor-for-deep-vein-2ycqyv268g.pdf

Hyperhomocysteinemia as a risk factor for deep-vein thrombosis

https://www.gastrojournal.org/article/0016-5085(95)90708-4/pdf

Intestinal permeability: an overview.

Background Venous and arterial thromboembolism occurs in only about one third of patients homozygous for homocystinuria, which suggests that other, contributory factors are necessary for the development of thrombosis in these patients. Factor V Leiden, an R506Q mutation in the gene coding for factor V, is the most common cause of familial thrombosis and could be a potentiating factor. Methods We determined activated partial-thromboplastin times in the presence and absence of activated protein C and tested for the factor V Leiden mutation in 45 members of seven unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. Results Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (age, 0.2 to 8 years). All six also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden has received warfarin therapy since birth and has not had thrombosis (age, 18 months). Of fo...

https://www.nejm.org/doi/pdf/10.1056/NEJM199603213341204

Coexistence of Hereditary Homocystinuria and Factor V Leiden — Effect on Thrombosis

Objective. The controversy over the incidence of developmental dysplasia of the hip (DDH) stems mainly from an ambiguity of criteria for defining a genuinely pathologic neonatal hip. In this study, we evaluate an algorithm we devised for the treatment of DDH, for its ability to identify those neonatal hips which, if left untreated, would develop any kind of dysplasia and, therefore, are to be included in the determination of DDH incidence. Methods. Clinical and ultrasonographic examinations for DDH were performed on 18 060 consecutive neonatal hips at 1 to 3 days of life. Newborns with skeletal deformities, neurologic/muscular disorders, and neural tube defects were excluded. Hips that featured any type of sonographic pathology were reexamined at 2 or 6 weeks, depending on the severity of the findings. Only hips in which the initial pathology was not improved or had deteriorated were treated; all others were examined periodically until the age of 12 months. Results. Sonographic screening of 18 060 hips detected 1001 instances of deviation from normal, indicating a sonographic DDH incidence of 55.1 per 1000. However, only 90 hips remained abnormal and required treatment, indicating a true DDH incidence of 5 per 1000 hips. All the others evolved into normal hips, and no additional instances of DDH were found on follow-up throughout the 12 months. Conclusions. The implementation of our protocol enables us to distinguish two categories of neonatal hip pathology: one that eventually develops into a normal hip (essentially sonographic DDH); and another that will deteriorate into a hip with some kind of dysplasia, including full dislocation (true DDH). This approach seems to allow for a better-founded definition of DDH, for an appropriate determination of its incidence, for decision-making regarding treatment, and for assessment of the cost-effectiveness of screening programs for the early detection of DDH. developmental dysplasia of the hip, incidence, neonatal screening, sonography.

Developmental Dysplasia of the Hip: A New Approach to Incidence

Objective. Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which primarily affects non-Ashkenazi Jews, Armenians, Arabs, and Turks. The gene responsible for the disease ( MEFV/FMF ) has been recently identified. Four common mutations in exon 10 of the MEFV gene seem to account for 86% of the DNA variations identified in patients with FMF. We conducted a phenotype/genotype correlation study in a mixed population of Jewish and Arab children with FMF. Study Design. Seventy patients clinically diagnosed as having FMF underwent molecular genetic studies using polymerase chain reaction and restriction endonuclease digestion methods to detect the presence of the four mutations (M694V, M680I, V726A, M694I). We then correlated the presence of each mutation with ethnic origin, age of onset, clinical manifestations, disease severity, and occurrence of amyloidosis. Results. The M694V mutation, which is predominant in non-Ashkenazi Jews, was found in 92% of our Jewish patients and in only 30% of the Arab patients. All four mutations were identified among 94% of the Arab patients, but with no particular prevalence for any one of them. The presence of a homozygous M694V mutation was significantly associated with a more severe form of the disease: the clinical onset of the disease manifested at an earlier age; the number of attacks per month was higher; the global assessment by the treating physician and the severity of pain scored higher; and arthritis was more frequent. Only patients with the M694V mutation had a family history of amyloidosis. No association was found between the type of mutation and the predominance of fever, abdominal pain, pleuritis, skin eruption, or response to colchicine in the clinical picture. Conclusions. Homozygosity for the M694V mutation, predominant among North African Jews, is associated with a severe course and prognosis for FMF. This mutation is less common among Arabs and, when present, occurs almost only in heterozygous form. In Arab patients, the disease tends to run a milder course and seems to bear a better prognosis. The phenotype/genotype patterns that are evident from our study of a mixed series of Jewish and Arab children with FMF might provide a rational basis for counseling about the natural history of the disease and for clinical treatment of FMF patients and their families.

https://pediatrics.aappublications.org/content/pediatrics/103/5/e70.full.pdf

Familial Mediterranean Fever: Clinical and Genetic Characterization in a Mixed Pediatric Population of Jewish and Arab Patients

A male infant is described showing all the major features of the oral-facial-digital syndrome (OFD): lobulated tongue with hypertrophic frena, fibrous bands extending into alveolar clefts, pseudocleft of upper lip, cleft palate, hypoplastic alae nasi, dystopia canthorum, various digital anomalies, and typical X-ray appearance of the skull. A partial agenesis of the corpus callosum with a lipoma was indicated by pneumoencephalography and angiography. The OFD syndrome is confined to females. In the present case an XXY chromosome constitution was demonstrated by cytogenetic studies. The occurrence of OFD and Klinefelter9s syndrome in one and the same person is ascribed to a very rare coincidence. OFD is considered to be due to an X-linked dominant mutant gene, with a recessive lethal effect. X-linkage is supported by the pattern of a more extreme lethal expression in hemizygous males versus viability of heterozygous females. An XXY individual is viable, presumably because of the normal allele which is active in a fraction of its cells. Other reports of males with OFD are critically evaluated.

The oral-facial-digital syndrome: a male-lethal condition in a boy with 47/xxy chromosomes

IN 1969 Rogers et al. described a case of unexplained anemia in association with diabetes mellitus and sensorineural deafness.1 The anemia responded only to pharmacologic closes of thiamine. Anothe...

Moshe Berant

Papers

Coexistence of Hereditary Homocystinuria and Factor V Leiden — Effect on Thrombosis

Developmental Dysplasia of the Hip: A New Approach to Incidence

Familial Mediterranean Fever: Clinical and Genetic Characterization in a Mixed Pediatric Population of Jewish and Arab Patients

The oral-facial-digital syndrome: a male-lethal condition in a boy with 47/xxy chromosomes

Thiamine-Dependent Beriberi in the “Thiamine-Responsive Anemia Syndrome”