Pituitary Stalk Interruption Syndrome - Clinical Presentation and Management of a Potentially Life-threatening Disease in Newborns.

Pituitary stalk interruption syndrome (PSIS) is a rare congenital disease resulting in hypopituitarism of variable degree. Serious courses, due to severe combined pituitary insufficiency, are even rarer and associated with a very early manifestation immediately after birth. First clinical signs are elusive and lead to delayed diagnosis and treatment, often resulting in life-threatening complications. Objective of the current report is to point out early leading symptoms and key issues of neonatal manifested PSIS to increase the awareness, improve the clinical management and thereby enable an early diagnosis and treatment to prevent further complications. This report presents and compares the clinical course and management of two male newborns with manifested PSIS. Early leading symptoms were the same in both patients, including recurrent hypoglycaemia, hyponatraemia, jaundice, cholestasis, sucking weakness and genital abnormalities. Patient 1 developed an infection-induced adrenal crisis, persistent substitution-dependent thrombocytopenia and convulsions due to severe hypoglycaemia in delayed PSIS diagnosis. In patient 2, due to recognised above-mentioned symptoms, endocrine testing and a subsequent cerebral magnetic resonance imaging were performed early and he was diagnosed and treated before major complications occurred. Genetic testing was performed in both patients. GLI2 gene mutation (NM_005270.5:c.2537del; p.(Pro846Argfs*66)) heterozygous was detected in patient 1. No mutation was found in patient 2. Conclusively, the early diagnosis of neonatal PSIS is indispensable in the treatment and prevention of the possible severe clinical manifestation of this orphan disease. Therefore, increased awareness for early leading symptoms and proper clinical management are crucial.

Frequency and Characteristics of MODY 1 (HNF4A Mutation) and MODY 5 (HNF1B Mutation): Analysis From the DPV Database.

Objective: To characterize the initial presentation and clinical course of patients with hepatocyte nuclear factor (HNF) 4A‒ and HNF1B‒MODY in a multinational registry. Design, Setting, and Participants: Within the Diabetes Patienten Verlaufsdokumentation (DPV) registry, 44 patients with HNF4A- and 35 patients with HNF1B-MODY were characterized and compared with patients <20 years old with type 1 diabetes (T1D)/type 2 diabetes (T2D). Main Outcome Measure: Clinical and laboratory parameters, therapy, metabolic control, and extrapancreatic symptoms in patients with HNF1B-MODY. Results: Patients with both MODY types were significantly older than patients with T1D at diagnosis (HNF4A, 13.8 years, and HNF1B, 13.5 years, vs T1D, 8.8 years; P < 0.0001). Mean C-peptide at diagnosis was higher for HNF4A-MODY than for T1D (1.8 vs 0.9 ng/mL; P < 0.01); 36.4% of patients with HNF4A-MODY and 65.7% of patients with HNF1B-MODY were treated with insulin, whereas 20.5% and 8.6% received oral antidiabetics only (P < 0.05 and P < 0.01 vs T2D). At the most recent visit, glycated hemoglobin levels were lower in HNF4A- and HNF1B-MODY (mean, 6.5% and 6.1%) than in T1D (7.9%; P < 0.0001). In 40% of patients with HNF1B-MODY, extrapancreatic symptoms were reported. Several clinical predictors previously described to differentiate between MODY and T1D or T2D were revalidated by logistic regression analyses in this cohort. Conclusion: The DPV registry enabled us to precisely characterize phenotype and treatment in these two rare MODY types. Although phenotype of HNF4A- and HNF1B-MODY showed distinct differences from those of T1D and T2D, 38% of patients were initially misclassified as having T1D or T2D.

Genotyping of coeliac-specific human leucocyte antigen in children with type 1 diabetes: does this screening method make sense?

OBJECTIVES: Due to a high linkage disequilibrium of diabetes and coeliac-specific human leucocyte antigen (HLA) genotypes, the prevalence of coeliac disease (CD) in children and adolescents with diabetes mellitus type 1 (T1D) is much higher than in the general population. Recently, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) revised new screening guidelines in which genotyping for coeliac-specific HLA alleles is recommended for high-risk patients as patients with T1D. The aim of our study was to investigate the frequency and distribution of coeliac-specific HLA genotypes in paediatric patients with T1D. STUDY DESIGN: HLA genotyping was performed on paediatric patients with T1D, recruited at the Medical University Hospital of Innsbruck and Graz. The test was done by PCR. Statistical analysis was performed with IBM-SPSS V.20. RESULTS: In 121 paediatric patients with T1D (52% male), mean age 13.3 (SD 3.9) years, mean age at diabetes diagnosis 7.4 (SD 3.8) and mean diabetes duration of 5.9 (SD 3.3) years, HLA genotyping was conducted. Ninety-two per cent showed positive HLA DQ2 and/or HLA DQ8 genotypes. Thirty-four per cent carried HLA DQ2, 33% were HLA DQ2+DQ8 positive and 25% of the patients showed positive results for HLA DQ8 alone. Only 8% had no coeliac-specific HLA markers. Four (3%) patients were diagnosed with CD. CONCLUSIONS: The majority of paediatric patients with T1D has positive coeliac-specific HLA genotypes DQ2 and/or DQ8. Therefore, genotyping for coeliac-specific HLA alleles as a first-line test in patients with T1D as recommended in the ESPGHAN guidelines does not seem reasonable. Screening for coeliac-specific antibodies needs to be performed on a regular basis for patients with T1D.

Needle detachment in a slim and physically active child with insulin pump treatment.

Insulin pump therapy (CSII) is well established in pediatric patients with type 1 diabetes. In childhood diabetes, insulin pump treatment shows considerable advantages such as fewer injections, increased flexibility, fewer hypoglycemic events and lower HbA1c levels. Side effects such as catheter obstruction, technical pump failure, and dermatological complications have been observed, but are rarely reported. The reported patient is a physically very active and slim 10-year-old boy with reduced subcutaneous fatty tissue. After strong muscular activity an accidental rupture of the infusion set and needle detachment occurred in October 2013. X-ray and ultrasound imaging localized the needle in the musculus rectus femoris dexter. The needle was kept in situ and oral antibiotic treatment to prevent inflammatory reaction was prescribed. Repeated ultrasound measurements documented that the needles position had remained unchanged. Steel needle catheters (Sure-T infusion set, 6 mm) positioned in a thin layer of subcutaneous fat tissue of the thigh, combined with intense sports activity can result in a needle rupture and penetration into the muscle. Careful monitoring provides an alternative to surgery and lowers the risk of muscular necrosis. Because of differences in the distribution of subcutaneous fat tissue, an individualized catheter selection is necessary in pump treatment for children and adolescents, requiring a variety of different catheter sets.

ALG8-CDG: novel patients and review of the literature.

BACKGROUND: Since 1980, about 100 types of congenital disorders of glycosylation (CDG) have been reported representing an expanding group of inherited disorders. ALG8-CDG (= CDG-Ih) is one of the less frequently reported types of CDG, maybe due to its severe multi-organ involvement with coagulation disturbances, edema, massive gastrointestinal protein loosing enteropathy, cataracts, and often early death. We report three additional patients, provide an update on two previously reported, and summarize features of ten patients reported in literature. RESULTS: Of 15 ALG8-CDG patients, three were homozygous and 12 compound heterozygous. There were multiple prenatal abnormalities in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13. CONCLUSION: In ALG8-CDG, isoelectric focusing of transferrin in serum or plasma shows an abnormal sialotransferrin pattern. The diagnosis is confirmed by mutation analysis in ALG8; all patients reported so far had point mutations or small deletions. The prognosis is generally poor. Thus, a timely and correct diagnosis is important for counselling.

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.

Enhanced activity of Akt in Teff cells from children with lupus nephritis is associated with reduced induction of tumor necrosis factor receptor-associated factor 6 and increased OX40 expression.

OBJECTIVE: The breakdown of peripheral tolerance mechanisms is central to the pathogenesis of systemic lupus erythematosus (SLE). Although true Treg cells in patients with SLE exhibit intact suppressive activity, Teff cells are resistant to suppression. The underlying mechanisms are incompletely understood. This study was undertaken to examine the Akt signaling pathway and molecules that may alter its activity in T cells in lupus patients. METHODS: The Akt pathway and its regulators were analyzed in Teff and Treg cells from children with lupus nephritis and controls using flow cytometry and real-time quantitative polymerase chain reaction. T cell proliferation was assessed by analysis of 5,6-carboxyfluorescein succinimidyl ester dilution. RESULTS: CD4+CD45RA-FoxP3(low) and FoxP3- Teff cells from children with lupus nephritis expressed high levels of activated Akt, resulting in the down-regulation of the proapoptotic protein Bim and an enhanced proliferative response. The induction of tumor necrosis factor receptor-associated factor 6 (TRAF6) was impaired, and TRAF6 levels inversely correlated with Akt activity. Although the expression of OX40 was enhanced on Teff cells from children with lupus nephritis compared to controls, OX40 stimulation failed to significantly increase TRAF6 expression in cells from patients, in contrast to those from healthy controls, but resulted in further increased Akt activation that was reversed by blockade of OX40 signaling. Moreover, inhibition of Akt signaling markedly decreased the proliferation of Teff cells from lupus patients. CONCLUSION: Our findings indicate that hyperactivation of the Akt pathway in Teff cells from children with lupus nephritis is associated with reduced induction of TRAF6 and up-regulation of OX40, which may cause Teff cell resistance to Treg cell-mediated suppression.

Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA.

The spliceosome, a ribonucleoprotein complex that includes proteins and small nuclear RNAs (snRNAs), catalyzes RNA splicing through intron excision and exon ligation to produce mature messenger RNAs, which, in turn serve as templates for protein translation. We identified four point mutations in the U4atac snRNA component of the minor spliceosome in patients with brain and bone malformations and unexplained postnatal death [microcephalic osteodysplastic primordial dwarfism type 1 (MOPD 1) or Taybi-Linder syndrome (TALS); Mendelian Inheritance in Man ID no. 210710]. Expression of a subgroup of genes, possibly linked to the disease phenotype, and minor intron splicing were affected in cell lines derived from TALS patients. Our findings demonstrate a crucial role of the minor spliceosome component U4atac snRNA in early human development and postnatal survival.

Incidence of neonatal diabetes in Austria-calculation based on the Austrian Diabetes Register.

BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare monogenic form of diabetes which is diagnosed in the first 6 months of life. Several studies in the last few years provide information on genetic causes for NDM. OBJECTIVE: The aim of this study was to identify all patients with diabetes in the first 6 months of life through the Austrian Diabetes Register, which is available since 1989. A retrospective data analyses was performed to calculate the current incidence of NDM. SUBJECTS AND METHODS: Ten patients were registered with diabetes onset within the first 6 months of life in the Austrian Diabetes Register. Evaluation of detailed clinical data was performed by sending a questionnaire to all diabetes centers. RESULTS: Ten patients from nine different families with NDM were diagnosed in Austria from 1989 until September 2007. Seven patients (one male, six females) had transient NDM (TNDM), three (two males, one female) showed a permanent course [permanent neonatal diabetes mellitus (PNDM)]. One had immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome and another showed aplasia of the pancreas; no genetic etiology was found in the third case. In three out of seven patients with a transient course of NDM a genetic diagnosis was possible. Two female siblings had activating point mutations in the ABCC8 gene, although one patient had paternal uniparental isodisomy of chromosome 6q24. One patient's family did not consent to genetic testing. CONCLUSIONS: The incidence of NDM in Austria is 1/160 949, with an incidence of 1/ 536 499 for PNDM and 1/229 928 for TNDM.

Mutations in PYCR1 cause cutis laxa with progeroid features.

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.

Using genomic inbreeding coefficient estimates for homozygosity mapping of rare recessive traits: application to Taybi-Linder syndrome.

The use of inbred patients whose exact genealogy may not be available is of primary interest in mapping genes involved in rare recessive diseases. We show here that this can be achieved by estimating inbreeding coefficients from the patients' genomic information and using these estimates to perform homozygosity mapping. We show the interest of the approach by mapping a gene for Taybi-Linder syndrome to chromosome 2q, with the use of a key patient with no genealogical information.

Progeria: a new kind of Laminopathy-- report of the First European Symposium on Progeria and creation of EURO-Progeria, a European Consortium on Progeria and related disorders.

Progeria is a rare, genetically determined condition characterized by accelerated aging in children. Its name is derived from Greek (Geron) and means "prematurely old". The classic type is the Hutchinson-Gilford Progeria Syndrome (HGPS), which was first described in England in 1886 by Dr. Jonathan Hutchinson (1) and again in 1904 by Dr. Hastings Gilford (2). Since then and up to now, very little advancement toward the understanding of this devastating disorder has been accomplished. In early 2003 a French group succeeded in identifying point mutations in the LMNA gene, encoding A-type lamins, as the main cause of this disorder. These results were concomitantly confirmed by an American group, who identified mutations in LMNA, working on a large cohort of patients (3,4). HGPS is thus the most severe disorder added to the expanding list of "laminopathies", diseases caused by mutations in the LMNA gene encoding A-type lamins. To date, up to ten disorders are associated with mutations in LMNA. These disorders are diverse, both in their symptomatology and pattern of inheritance (see below and table 1). Due to the extremely low prevalence of progeria and the putative functional links between progeria and other premature aging disorders, setting-up a network about these disorders has become an absolute necessity. A reunion of families with a child affected with progeria, gathered within the European Progeria Family Circle, was held from September 25th to 29th 2003 in Magdeburg, Germany. In parallel to this event, a scientific symposium centered on clinical and molecular update of HGPS and related syndromes was organised. Several international experts, including clinical and molecular geneticists, cell biologists involved in the field of laminopathies, as well as paediatricians and other physicians with clinical experience in diagnosis, treatment and research on progeria and progeria-like syndromes presented their experience as well as their research projects and yet unpublished results. The main discussed topics as well as the developing research fields on progeria and related premature ageing disorders will be presented here.