Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping

Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.     

Argininosuccinic aciduria. A new case revealed by psychiatric disorders

The case of a 4 years old boy, hospitalized for an unexplained coma, is reported. He is the first child of a non-consanguin couple. The psychomotor development of this child was considered as normal up to the age of 18 months; then, a delay in language development, behaviour disorders with an important instability interrupted by episodes of somnolence, were observed. This child was treated for psychotic disorders. At the age of 3 and half, he had two episodes of seizures associated with fever. He was hospitalized for a 24 hours coma (4 years old). An hepatomegaly and a dry, brittle hair were then observed. Hyperammonemia was made obvious by a protein tolerance test. The diagnosis of argininosuccinate lyase (ASAL) deficiency was based on the increased levels of ASA in plasma and urine. The deficiency was proved by a fibroblast culture. With protein restriction, hepatomegaly disappeared, hair became normal, the behaviour disorders and the delay in language development was improved. However, some school difficulties persist. This case shows that an hereditary metabolic syndrome can be revealed by psychotic like symptoms in childhood.     

Amelioration by copper supplementation of mutant gene effects in the crinkled mouse.

The possibility of a relationship between the autosomal recessive mutant gene crinkled in mice and copper metabolism was investigated by examining the effect of copper supplementation during pregnancy and lactation on the expression of the gene in homozygous mutant young. Survival of mutant mice to 30 days of age was doubled by feeding their mothers a high copper diet (500 ppm copper) during pregnancy and lactation, as compared with controls (6-11 ppm dietary copper). High dietary copper also prevented the lag in pigment development characteristic of the mutants. Furthermore, skin and epidermal thickness and hair bulb development were nearly normal in the high copper group, in contrast to thin skin and paucity of hairs in controls. Supplementation with manganese did not have these effects. Scanning electron micrographs showed the presence of three types of hair abnormalities in crinkled mutants, monilethrix, pili torti, and possibly trichorrhexis nodosa. The results show that increased availability of copper favorably altered the expression of the mutant gene, and demonstrate the interaction of a gene and a trace metal in development.     

Early Diagnosis of Extrahepatic Biliary Atresia in an Open-Access Medical System

Introduction

Biliary atresia (BA) is the most common cause of cholestatic jaundice in infancy. Early diagnosis and surgical management, ideally before 60 days of age, result in improved outcomes. We aimed to determine the age at diagnosis of BA in the Military Health System (MHS) and to compare the age at diagnosis by access to care models. We hypothesized that children with BA receiving primary care in military facilities have an earlier age at diagnosis due to decreased economic and access barriers.

Methods

Data for all Tricare enrollees born in fiscal years 2004–2008 with a diagnosis of BA were extracted from MHS databases. Non-parametric tests, Kaplan-Meier curves and log rank tests compared differences in age at diagnosis by type of primary care facility, gender, prematurity and presence of additional anomalies.

Results

64 subjects were identified within the five year period. Median age at diagnosis was 40 days [range 1–189], with 67% diagnosed by 60 days and 80% by 90 days. 45 (70%) received civilian primary care within the MHS. There was no difference in the median age at diagnosis between subjects in the MHS with civilian primary care vs. military primary care (37 days [1–188] vs. 46 days [1–189]; p = 0.58).

Conclusion

In the MHS, two-thirds of infants with biliary atresia are diagnosed prior to 60 days of life. Gender, prematurity or presence of additional anomalies do not affect the timing of diagnosis. Civilian and military primary care models within the MHS make timely diagnoses of biliary atresia at equivalent rates.     

White monkey syndrome in infant baboons (Papio species)

Over 23 months, zinc toxicosis was diagnosed in 35 baboons aged 5-12 months in one galvanized metal and concrete cage complex with conditions that led to excessive exposure to environmental zinc. Clinical signs included reduced pigmentation of hair, skin, and mucous membranes (whiteness), alopecia, dehydration, emaciation, cachexia, dermatitis, diarrhea and, in six cases, severe gangrenous dermatitis of extremities. The syndrome was characterized by pancytopenia, elevated zinc and low copper serum concentrations, low vitamin D and bone-specific alkaline phosphatase levels, and atypical myelomonocytic proliferation of bone marrow. This syndrome emphasizes the importance of proper husbandry and cage design and indicates the potential of infant baboons as a model to study the effects of excessive zinc on development. This is the first report describing the epidemiologic and clinical presentation of zinc toxicosis in infant baboons in captivity.     

Age at diagnosis, body mass index and physical morbidity in children and adults with the Prader-Willi syndrome

Age at diagnosis, Body Mass Index and physical morbidity in children and adults with the Prader-Willi syndrome: The medical findings of a population of 54 Prader-Willi patients with a molecular confirmed diagnosis are discussed. In the age group aged 18 or younger, a reasonably good control of weight as measured by Body Mass Index (BMI) is found. This is probably due to the fact that diagnosis was made at an early age and intensive diet management was started early. Despite their relatively low BMI, these children remain at high risk for developing scoliosis requiring active treatment (28% of the children). Adults (older than 18) diagnosed at the age of 10 or later have a high risk for developing obesity and obesity related health problems such as hypertension (38%), non-insulin dependant diabetes mellitus (11%) and cardio respiratory failure (16%).     

The effect of treatment of twin-twin transfusion syndrome on the diagnosis-to-delivery interval.

No randomised controlled trials of treatment of twin-to-twin transfusion syndrome (TTTS) exist. Since severely preterm neonatal survival has increased over time, survival as an outcome measure is confounded by improvements in neonatal care. The diagnosis-to-delivery interval is a measure of success of treatment independent of improvements in neonatal care. We wished to evaluate whether treatment of TTTS is associated with a lengthening of the diagnosis-to-delivery interval. MEDLINE search was performed supplemented by careful reference review. All TTTS series were included where the following information on each patient was available: survival, fetal demise, gestational age at diagnosis and diagnosis-to-delivery interval in days. Inclusion criteria: gestational age at diagnosis < 29 weeks and diagnosis by ultrasound in the absence of maternal symptoms. Cases undergoing multiple types of treatment were excluded. Eight publications met inclusion criteria and included the following cases: controls (n = 16), amnioreduction (n = 61), septostomy (n = 12), and fetoscopic laser occlusion of chorioangiopagus vessels (n = 51). There was no difference in the diagnosis-to-delivery interval, overall survival, at least one survivor, or number of fetal deaths between the four groups. Logistic regression using at least one survivor as the dependent variable revealed a positive association with gestational age at diagnosis and with diagnosis-to-delivery interval, a negative correlation with fetal death, and no correlation with treatment group. We conclude that there is no difference in diagnosis-to-delivery interval or survival for any treatment for TTTS compared to expectant management. The lack of significance appears to be due to small sample sizes.     

Tmprss3, a transmembrane serine protease deficient in human DFNB8/10 deafness, is critical for cochlear hair cell survival at the onset of hearing

Mutations in the type II transmembrane serine protease 3 (TMPRSS3) gene cause non-syndromic autosomal recessive deafness (DFNB8/10), characterized by congenital or childhood onset bilateral profound hearing loss. In order to explore the physiopathology of TMPRSS3 related deafness, we have generated an ethyl-nitrosourea-induced mutant mouse carrying a protein-truncating nonsense mutation in Tmprss3 (Y260X) and characterized the functional and histological consequences of Tmprss3 deficiency. Auditory brainstem response revealed that wild type and heterozygous mice have normal hearing thresholds up to 5 months of age, whereas Tmprss3(Y260X) homozygous mutant mice exhibit severe deafness. Histological examination showed degeneration of the organ of Corti in adult mutant mice. Cochlear hair cell degeneration starts at the onset of hearing, postnatal day 12, in the basal turn and progresses very rapidly toward the apex, reaching completion within 2 days. Given that auditory and vestibular deficits often co-exist, we evaluated the balancing abilities of Tmprss3(Y260X) mice by using rotating rod and vestibular behavioral tests. Tmprss3(Y260X) mice effectively displayed mild vestibular syndrome that correlated histologically with a slow degeneration of saccular hair cells. In situ hybridization in the developing inner ear showed that Tmprss3 mRNA is localized in sensory hair cells in the cochlea and the vestibule. Our results show that Tmprss3 acts as a permissive factor for cochlear hair cells survival and activation at the onset of hearing and is required for saccular hair cell survival. This mouse model will certainly help to decipher the molecular mechanisms underlying DFNB8/10 deafness and cochlear function.     

Intensive Care Society's APACHE II study in Britain and Ireland--II: Outcome comparisons of intensive care units after adjustment for case mix by the American APACHE II method.

OBJECTIVES--To compare outcome between intensive care units in Britain and Ireland both before and after adjustment for case mix with the American APACHE II method and to validate the American APACHE II method in Britain and Ireland. DESIGN--Prospective, cohort study of consecutive admissions to intensive care units. SETTING--26 general intensive care units in Britain and Ireland. SUBJECTS--8796 admissions to the study intensive care units. MAIN OUTCOME MEASURE--Death or survival at discharge from intensive care unit and hospital. RESULTS--At discharge from both intensive care unit and hospital there was a greater than twofold variation in crude mortality between the 26 units. After adjustment for case mix, variations in mortality were still apparent. For four intensive care units the observed numbers of deaths were significantly different from the number predicted by the American APACHE II equation. The overall goodness of fit, or predictive ability, of the APACHE II equation for the British and Irish data was good, being only slightly inferior to that obtained when the equation was tested on the data from which it had been derived. When patients were grouped by various factors such as age and diagnosis, the equation did not adjust across the subgroups in a uniform manner. CONCLUSIONS--The American APACHE II equation did not fit the British and Irish data. Use of the American equation could be of advantage or disadvantage to individual intensive care units, depending on the mix of patients treated.     

Design and development of a series of borocycles as selective,covalent kallikrein 5 inhibitors

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.     

Changes in the content of individual lipid classes of a lichen <Emphasis Type="Italic">Peltigera aphthosa</Emphasis> during dehydration and subsequent rehydration

A lichen Peltigera aphthosa (L.) Willd. was subjected to a short-term (7 days) or a long-term (180 and 540 days) dehydration followed by rehydration. Then the composition and content of lipids, as well as the rate of their metabolism (the rate of sodium 2-¹⁴C-acetate incorporation) were investigated. The long-term dehydration resulted in a dramatic decrease in the content (per dry wt) of major extrachloroplastic phospholipids, mainly phosphatidylcholines and phosphatidylethanolamines. The rehydration of lichen thalli after a short-term and long-term dehydration also resulted in an enhanced breakdown of these lipid molecules; however, it was accompanied by their rather intense in vivo synthesis, which was decreased after long-term dehydration. In contrast to phospholipids, the betaine lipids, diacylglyceroltrimethylhomoserines (DGTSs), were involved in metabolic processes to a far lesser extent. In the course of rehydration, their content was virtually unchanged and decreased only after 540 days of dehydration. The rate of incorporation of sodium 2-¹⁴C-acetate into the DGTS molecules was moderate and did not change even after long-term dehydration. Glycolipids were characterized by a fair tolerance to hydrolytic processes and by an increase in the rate of their synthesis after 540 days of the lichen dehydration. Responses of neutral lipids to dehydration turned out to be different. The long-term dehydration (for 540 days) was accompanied by a decrease in the contents of free sterols and sterol esters, whereas the contents of di- and triacylglycerols remained unchanged. Rehydration resulted in a decrease in diacylglycerol and sterol ester contents. All neutral lipids were characterized by a dramatic decrease in the rate of de novo synthesis after long-term dehydration. It was suggested that the tolerance of lichen to long-term dehydration was appreciably determined by the tolerance of its phycobiont, in this case, a green alga Coccomyxa sp.; the bulk of its lipids was characterized by a minimum rate of breakdown and, at the same time, by a stable synthesis.Translated from Fiziologiya Rastenii, Vol. 52, No. 1, 2005, pp. 43–50.Original Russian Text Copyright © 2005 by Kotlova, Sinyutina.     

Bloom's syndrome. Discussion of the diagnosis concerning two cases of terminal leukemia in a sibship (author's transl)

Two brothers developed acute leukemia, one at the age of 7 months and the other at the age of 14 months. Both suffered from a staturoponderal retardation and the same malformation syndrome. The karyotype carried out only on the second child revealed breaks and chromatid changes. A diagnosis of Fanconi's anaemia can be discarbed since no blood cytopenia preceded the leukemia. Finally, the diagnosis of Bloom's syndrome prevailed despite the absence of telangiectatic erythema and the atypical chromosomal anomalies.     

Early fractures and occult hyperthyroidism: McCune-Albright syndrome?

McCune-Albright syndrome (MAS) is a sporadic disease characterized by fibrous bone dysplasia, café-au-lait spots and hyperfunctional endocrinopathies. We report a 2.5-year-old child with MAS with an early and nonclassic onset. He was admitted to our attention for frequent fractures without clinical signs of endocrinopathies, found to have asymptomatic, nonautoimmune hyperthyroidism. The diagnosis of MAS was based on RX and MR imaging associated with hyperthyroidism. It is not clear if there was a correlation between the severity of bone disease and the presence of thyroid disorder. At the moment no standard treatment exists for bone fibrous dysplasia and hyperthyroidism in children before the age of 6 years.     

Morphological changes in hair melanosomes by aging

Various changes appear in hair by aging, and graying is the most remarkable one. Changes in melanocytes have been well studied as the cause; however, little is known about the change in melanosomes which have a role of carrying melanin pigments into hair shafts. Using pigmented hairs of Japanese females from their age of 4–75, I isolated melanosomes and observed them. As a result, I found a significant change in the morphology of hair melanosomes with age. They were ellipsoidal on the whole and there was no age dependence in the major axis, while the minor axis significantly increased and its frequency distribution broadened with age. The anticipated volume of the melanosome of the oldest person hairs was about twice larger than that of child hairs. This enlargement of melanosome seems to be a cause of the age‐related color change in pigmented hairs from brown to black.     

Harlequin ichthyosis — difficulties in prenatal diagnosis

Ichthyoses belong to the group of genodermatoses, characterized by hyperkeratosis and desquamation of the epidermis. Clinical manifestation is heterogeneous and depends on the type of the disease. Harlequin foetus is the most severe form of congenital ichtyosis, inherited as an autosomal recessive trait. The disfunction of the epidermis begins prenatally. Neonates are often born prematurely, in severe condition. At present better care and treatment prolong the length and quality of children's life. We report a case of harlequin ichthyosis. Parents were healthy and there was no history of ichthyosis or other congenital anomalies in the family. Sonography at the 26th week of gestation revealed anomalies of the fetal face; however, the diagnosis of harlequin ichthyosis was not established prenatally. The male child was born alive at the 37th week of the third pregnancy, with birth weight of 2900 g. Typical features of harlequin ichthyosis were present at birth. Intensive neonatological care was necessary. The child survived and at the time of the report was 6 months old and in good condition.     

Intensive Care Society's APACHE II study in Britain and Ireland--I: Variations in case mix of adult admissions to general intensive care units and impact on outcome.

OBJECTIVES--To describe the extent of variation in the case mix of adult admissions to general intensive care units in Britain and Ireland and investigate the impact of such variation on outcome. DESIGN--Prospective, cohort study of consecutive admissions to intensive care units. SETTING--26 general intensive care units in Britain and Ireland. SUBJECTS--9099 admissions to the intensive care units studied. MAIN OUTCOME MEASURE--Death or survival at discharge before and after adjustment of case mix (age, history of chronic conditions, surgical status, diagnosis, and severity of illness) according to the APACHE II method. RESULTS--Important differences in case mix were found, with large variations between the units. Hospital mortality was significantly associated with most of the case mix factors investigated. CONCLUSIONS--Comparing crude death rates in hospital between intensive care units may be misleading indicators of performance. The collection of data on case mix needs to be standardised and differences in case mix adjusted for when comparing outcome between different intensive care units.     

Transient pseudohypoaldosteronism with complex malformation of internal genitalia. A case report

At the age of 3 weeks, a girl presenting with acute dehydration was admitted to our hospital. Clinical and laboratory findings revealed malformations of the genitourinary tract, an acute urinary infection and electrolyte disturbances (severe hyponatremia at 115 mmol/l and mild hyperkalemia at 5.6 mmol/l). According to anamnestic data, the child was born to healthy, nonconsanguineous parents. Vaccum extraction was done in the 38th gestational week due to pathological cardiotocography (CTG) findings. Auxological parameters were within the normal range for gestational age. Normal values for 17-OH progesterone and ACTH ruled out congenital adrenal hyperplasia (CAH). Pathologically high aldosterone and plasma renin activity (PRA) confirmed the diagnosis of pseudohypoaldosteronism with salt-wasting crisis which proved to be transient.     

Subacute thyroiditis presenting as Cushing's syndrome. Case report.

Subacute thyroiditis is a benign, self-limited disorder characterized by hyperthyroidism that resolves spontaneously. Although cortisol metabolism is accelerated in hyperthyroidism, cortisol levels are usually normal. We describe a child with subacute thyroiditis whose presenting complaints and preliminary evaluation suggested a diagnosis of Cushing's syndrome. There was spontaneous improvement in the signs and symptoms with concomitant normalization of laboratory values. We conclude that hypercortisolism may be a manifestation of hyperthyroidism, and the evaluation of Cushing's syndrome should include thyroid function tests.     

Elejalde syndrome: clinical and histopathological findings in an Egyptian male

Elejalde syndrome is a rare disorder. An Egyptian male patient with Elejalde syndrome is presented. He had silvery hair since birth, generalized hypopigmentation, severe primary central nervous system dysfunction, and normal hematological and immunologic profiles. Magnetic resonance of the brain revealed prominent cerebellar atrophy with mild fronto-parietal cortical atrophic changes. Microscopic analysis of his hair showed melanin clumps irregularly distributed along the hair shafts, and a skin biopsy showed increased pigmentation in the basal melanocytes. The differential diagnosis of silvery hair disorders includes Elejalde syndrome, Griscelli and Chediak-Higashi syndromes. In the present report, we review the literature on Elejalde syndrome and discuss the differential diagnosis.