José L. Olivares

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

Cardiac findings in adolescents with anorexia nervosa at diagnosis and after weight restoration

The aim of this study was to compare heart abnormalities in a group of young women with anorexia nervosa at diagnosis and after weight restoration. A total of 40 young women with anorexia nervosa were evaluated, at baseline, (diagnosis) and follow-up (9 to 18 months later) and matched with 40 healthy women of the same age and of normal weight. QT interval was measured from surface electrocardiograms. QT dispersion was defined as the difference between maximum QT and minimum QT occurring in any of the 12 leads. Left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left ventricular mass, left ventricular mass index, cardiac output, fractional shortening and fractional ejection, were measured by echocardiography. In anorexia nervosa patients, corrected QT interval and QT dispersion, significantly decreased from baseline to follow-up. Left ventricular end-diastolic dimension, left ventricular mass index, and cardiac output, in anorexia nervosa were significantly lower at diagnosis than at follow-up after weight restoration. Conclusion:Adolescents with anorexia nervosa have significant functional and structural cardiac abnormalities; weight gain was associated with improvement. Appropriate attention should be paid to cardiac involvement.

Mutations and Variants in the Cohesion Factor Genes NIPBL, SMC1A, and SMC3 in a Cohort of 30 Unrelated Patients With Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) manifests facial dysmorphic features, growth and cognitive impairment, and limb malformations. Mutations in three genes (NIPBL, SMC1A, and SMC3) of the cohesin complex and its regulators have been found in affected patients. Here, we present clinical and molecular characterization of 30 unrelated patients with CdLS. Eleven patients had mutations in NIPBL (37%) and three patients had mutations in SMC1A (10%), giving an overall rate of mutations of 47%. Several patients shared the same mutation in NIPBL (p.R827GfsX2) but had variable phenotypes, indicating the influence of modifiers in CdLS. Patients with NIPBL mutations had a more severe phenotype than those with mutations in SMC1A or those without identified mutations. However, a high incidence of palate defects was noted in patients with SMC1A mutations. In addition, we observed a similar phenotype in both male and female patients with SMC1A mutations. Finally, we report the first patient with an SMC1A mutation and the Sandifer complex.

Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2 : from genotype to phenotype

Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype–phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single family segregating a submicroscopic deletion of 11p11.2, including ALX4. We explored the correlations between skull defect size and age, gene, and mutation type, and reviewed additional phenotypic manifestations. Four PFM cases had mutations in either ALX4 or MSX2; including previous families, we have identified six ALX4 and six MSX2 mutations, accounting for 11/13 familial, but only 1/6 sporadic cases. The deletion family confirms the delineation of a mental retardation locus to within 1.1 Mb region of 11p11.2. Overall, no significant size difference was found between ALX4- and MSX2-related skull defects, but the ALX4 mutation p.R218Q tends to result in persistent CB and is associated with anatomical abnormalities of the posterior fossa. We conclude that PFM caused by mutations in ALX4 and MSX2 have a similar prevalence and are usually clinically indistinguishable. Mutation screening has a high pickup rate in PFM, especially in familial cases, but is not indicated in CRS.

Gender differences in newborn subcutaneous fat distribution.

The pattern and distribution of subcutaneous fat in term and preterm newborns has been assessed by skinfold thicknesses (ST), describing gender and gestational age variations. Weight, length and ST (triceps, biceps, subscapular and suprailiac) were measured in 4634 neonates (2445 males and 2189 females) aged from 32 to 41 gestational weeks. Central to total skinfold ratio (CTS), (suprailiac + subscapular)/sum of 4 ST, was calculated. Males were heavier and longer than females. The sum of 4 ST and CTS was higher in females at every gestational age (with significant differences from 35 weeks) and also the sum of 4 ST per kg body weight (P<0.05 from 32–33 weeks). Throughout the gestational period, ST increased significantly (P<0.0001) but CTS did not show variations, neither in males nor in females. Conclusion: term and preterm females have a more centralised pattern and more amount of subcutaneous fat than males. Central to total skinfold ratio must be considered as an index of centripetal fat store which is independant of gestational age.

Reference levels for 17-hydroxyprogesterone, 11-desoxycortisol, cortisol, testosterone, dehydroepiandrosterone sulfate and androstenedione in infants from birth to six months of age.

Reference plasma adrenal steroid levels during early infancy are frequently used to verify hormone measurements when any adrenal abnormality is suspected. We aim to obtain longitudinal reference plasma levels for 17-hydroxyprogesterone (17OHP), 11-desoxycortisol (11DOC), cortisol, dehydroepiandrosterone sulfate (DHEAS), testosterone, and androstenedione in healthy infants from birth to 6 months of age. In 138 term infants, 80 males and 58 females, plasma steroid levels were measured using specific RIA procedures at birth and on the 3rd, 15th, 30th, 60th, 90th, 120th, 150th, and 180th days of life. Smoothed percentiles for each variable were calculated according to the LMS method (LMS program version 1.16, Institute of Child Health, London). Except for cortisol, plasma levels of adrenal steroids decreased progressively from birth to 6 months of age. Plasma concentrations of 17OHP, 11DOC, and cortisol did not show gender differences, but testosterone and androstenedione were significantly higher in boys, and DHEAS levels were higher in girls. Longitudinal reference plasma levels for 17OHP, 11DOC, cortisol, DHEAS, testosterone, and androstenedione have been described in an adequate sample of healthy infants from birth to 6 months of age. These standards, displayed as smoothed percentiles, may be used as reference values in the management of congenital endocrine (adrenal or gonadal) abnormalities that appear in the first weeks of life.

Alteraciones cardiológicas en mujeres adolescentes con anorexia nerviosa

Results. QT and corrected QT intervals were significantly greater in patients with anorexia nervosa than in the control group. QT dispersion and corrected QT dispersion were significantly greater in anorexia nervosa than in the control group (QTd, 59.3 ± 23.0 vs 38.4 ± 8.0 ms; p = 0.000; QTcd, 56.5 ± 24.2 vs. 40.3 ± 21.8 ms; p = 0.011). Left ventricular mass was significantly lower in young women with anorexia nervosa. We found a significant relationship between body mass index and left ventricular mass index, and between the former and corrected QT dispersion. Conclusions. Adolescents with anorexia nervosa show significant cardiac disorders in comparison to healthy women of the same age. This finding may be a useful indicator of the risk of arrhythmia and sudden death in patients with anorexia nervosa.

Vitamin B12 and Folic Acid in Children with Intestinal Parasitic Infection

Objective: To determine prospectively plasma levels of vitamin B12 and folic acid in children with intestinal parasitic infection before and three months after antiparasitic treatment. Methods: 3036 stool samples were collected from 1959 children and 939 cello-tape anal swabs were taken from 688 children for intestinal parasite investigation. Of these, 155 children were identified as having a parasitic infection; however, only 86 were followed up during this study: 26 children with Giardia lamblia infection were treated with tinidazole and metronidazole, pyrantel pamoate was used in the treatment of 40 children with Enterobius vermicularis, and 20 patients infected with Cryptosporidium parvum received only symptomatic treatment. Vitamin B12 and folic acid levels were measured by radioimmunoassay, before and three months after the completion of treatment. Results: Vitamin B12 serum concentrations did not show any significant differences among the three groups. There was a significant increase in vitamin B12 serum concentrations after three months of anti-parasitic treatment (630.57 ± 200.97 vs. 667.97 ± 181.55 pg/dL, p = 0.002, n = 86). Paired analysis in each group showed only significant increases for vitamin B12 in the Giardia lamblia group and in the Enterobius vermicularis group. No statistically significant differences were found for folic acid serum concentrations before and three months after treatment. Conclusions: Patients with symptomatic infection by Giardia lamblia and Enterobius vermicularis have lower vitamin B12 levels than asymptomatic patients. This could reflect a more affected intestinal mucous. These results could present the opportunity to treat these parasitic infections and to use vitamin B12 supplementation in symptomatic children with Giardia lamblia and Enterobius vermicularis infection.

Epidermal naevus syndrome and hypophosphataemic rickets: description of a patient with central nervous system anomalies and review of the literature

Abstract The epidermal naevus syndrome (ENS) is a rare dermatological condition consisting of congenital epidermal nevi associated with anomalies in the central nervous system, bones, eyes, hear or genito-urinary system. We report a new case of ENS associated with hypophosphataemic rickets. The girl was born with a mixed-type epidermal naevus and skeletal anomalies. Hypophosphataemic rickets was diagnosed at the age of 2.5 years. At 14 years of age, MRI of the head demonstrated right brain hypotrophy, a left temporal arachnoid cyst and asymetric lateral ventricles. We reviewed the literature and found 13 reported cases of ENS associated with hypophosphataemic rickets. Conclusion We report a further patient with epidermal naevus syndrome and hypophosphataemic rickets, followed from birth to the age of 15 years, who had structural central nervous system anomalies with normal intellectual functioning. A comprehensive neurological work up is recommended in patients with epidermal naevus syndrome.

Electrocardiographic and echocardiographic findings in malnourished children.

Objective: To compare heart abnormalities in a group of malnourished children with a control group and to describe their predictive variables. Methods: Thirty children with malnutrition were matched with thirty healthy children. Anthropometry, plasma levels of albumin and electrolytes were determined. Among others, corrected QT interval (QTc) and QT dispersion (QTd: difference between the maximum and the minimum QT) were measured in 12-lead electrocardiogram; and left ventricular mass (LVm) and left ventricular mass index (LVmi) were measured by echocardiography. Regression analyses were performed with cardiac findings as dependent variables and anthropometric and biochemical data as independent variables. Results: Plasma levels of albumin, potassium and calcium were lower in malnourished children. QTc and QTd were significantly greater in patients with malnutrition than in controls (QTc: 445.9 ± 31.4 vs. 400.9 ± 17.7 ms, p = 0.000; QTd: 76.4 ± 34.1 vs. 47.9 ± 10.2 ms, p = 0.000). LVm and LVmi were significantly lower in malnourished children (LVm: 55.3 ± 10.3 vs. 71.4 ± 6.9 g, p = 0.000; LVmi: 46.5 ± 6.6 vs. 60.5 ± 4.9 g/m2, p = 0.000). The body mass index (kg/m2) was the most powerful predictor of the variability in QTc (39.1%), LVm (48.1%) and LVmi (51.2%). Conclusions: Important electrocardiographic and echocardiographic abnormalities have been found in malnourished children associated with their nutritional status. Special precaution must be taken about the possibility of occurrence of arrhythmias and sudden death related with malnutrition.