Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation

Permanent neonatal diabetes mellitus is a rare disorder known to be caused by activating mutations in KCNJ11 or ABCC8, inactivating mutations in INS, or very rarely in GCK or insulin promotor factor-1 (IPF-1) genes. We report a patient with permanent neonatal diabetes mellitus and severe exocrine pancreatic insufficiency. Ultrasound examination revealed pancreatic agenesis with a suggestion of a small amount of tissue in the head of the pancreas. Genetic testing revealed that the neonate had a homozygous Pro63fsX60 IPF-1 mutation. This is the second reported case of neonatal diabetes mellitus secondary to a homozygous mutation in the IPF-1 gene and supports the previously proposed biological role of IPF-1 in the pancreatic development in human.     

Pancreatic agenesis as cause for neonatal diabetes mellitus

BACKGROUND: Pancreatic agenesis is a rare cause of neonatal diabetes mellitus and the knowledge about the clinical features is sparse. A patient with pancreatic agenesis and double outlet right ventricle is reported. This association has not previously been reported. In addition a synopsis of the patients (n = 14) with pancreatic agenesis who have hitherto been described is given. METHOD: We studied one patient and obtained information on 13 additional patients with pancreatic agenesis by reviewing literature. RESULTS: Literature review: In one patient the pregnancy was terminated at 19 weeks. 31 % (4/13) of the infants died in the first week and 69 % (9/13) in the first six weeks of live, 17 % (2/12) were born preterm and 83 % (10/12) at term, 93 % (13/14) had severe intrauterine growth restriction, onset of diabetes was in 6 out of 10 infants during the first two days of live, ketonuria is rare and has been reported only once. 64 % (9/14) of the infants with pancreatic agenesis had additional malformations mainly of the biliary system (50 %) and/or the heart (36 %). 31 % (4/13) of the infants survived the neonatal period and developed normally. Failure to thrive was compensated by catch-up growth after replacement of pancreatic enzymes and surgical correction of the cardiac malformation. CONCLUSIONS: Pancreatic agenesis is a clinical entity characterized by severe intrauterine growth retardation, early onset of permanent neonatal diabetes mellitus without ketoacidosis, failure to thrive due to pancreatic exocrine dysfunction and associated malformations mainly of the biliary system or of the heart. Because of the high neonatal mortality, awareness of pancreatic agenesis as a possible cause of severe intrauterine growth restriction is important for the optimal treatment of diabetes mellitus, exocrine pancreatic insufficiency and the associated malformations.     

Neonatal diabetes mellitus because of pancreatic agenesis with dysmorphic features and recurrent bacterial infections

Abstract:  Pancreatic agenesis is a rare cause of neonatal diabetes mellitus (NDM). It can be associated with malformations of the heart, the biliary tract, and the cerebellum. We report an infant with NDM because of pancreatic agenesis, intra-uterine growth retardation, dysmorphic features, and recurrent bacterial infections. He was born to healthy consanguineous parents. With adequate replacement of insulin and pancreatic enzymes, his blood glucose levels were controlled and his weight slowly increased. However, he continued to develop recurrent serious bacterial infections and died at the age of 11 months with sepsis and respiratory failure. Analysis of the PTF1A and PDX1 genes, which have been associated with congenital agenesis of the pancreas, did not reveal any mutation. Genetic abnormalities of chromosome 6 associated with transient neonatal diabetes as well as mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic potassium channel were also excluded as a cause of the NDM in this patient. The association of permanent neonatal diabetes because of pancreatic agenesis, dysmorphism, and non-specific immunodeficiency is previously undescribed and may represent a new possibly autosomal recessive syndrome.     

Neonatal diabetes mellitus due to pancreas agenesis: a new case report and review of the literature

Neonatal diabetes mellitus (NDM) is a rare condition (1:400 000 neonates) defined as hyperglycemia occurring in the first months of life, lasting more than 2 wk and requiring insulin for management. We here report on a 33-month-old girl with pancreatic agenesis, an extremely rare cause of permanent neonatal diabetes mellitus (PNDM). Timely diagnosis and adequate treatment of both endocrine and exocrine insufficiency may permit survival and normal development.     

Paucity of intrahepatic bile ducts,solitary kidney and atrophic pancreas with diabetes mellitus: Atypical Alagille syndrome?

Abstract A child with the tentative diagnosis of Alagille syndrome is reported. Additional renal abnormalities are unilateral kidney agenesis and a kidney with subcortical cysts with decreased function. At the age of 5 years, insulin-dependent diabetes mellitus developed, with the pancreas being atrophic and negative pancreatic islet cell antibodies.Conclusion This observation extends the picture of Alagille syndrome and suggests an overlap with renal-hepatic-pancreatic dysplasia (Iyemark syndrome).     

A novel mutation in GATA6 causes pancreatic agenesis

Heterozygous mutations in GATA6 have been linked to pancreatic agenesis and cardiac malformations. The aim of this study was to describe a new mutation in GATA6 in an infant with pancreatic agenesis, associated with truncus arteriosus and absent gallbladder. Clinical data were obtained from chart review. Gene sequencing was performed on genomic DNA. The patient was a female infant diagnosed shortly after birth with a severe cardiac malformation, absent gallbladder, anomalous hepatic blood flow, unilateral hydronephrosis and hydroureter, neonatal diabetes, and pancreatic exocrine insufficiency. Despite prolonged intensive management care, she died at 3 months of age because of cardiac complications. Analysis of her genomic DNA revealed a novel missense mutation of GATA6. The novel mutation described in this case extends the list of GATA6 mutations causing pancreatic agenesis and cardiac malformations.     

Caudal regression syndrome - caudal agenesis

BACKGROUND: Neural tube defects are caused by complex genetic and environmental factors. The congenital anomaly most specific to pregnant women with diabetes mellitus is caudal regression syndrome. PATIENT: A 4-year-old boy with a history of mild delay in motor development presented with primary enuresis and encopresis. On physical examination, he had no sensory and motor deficits, but a short anal cleft. On questioning, the mother reported insulin-dependent diabetes mellitus during pregnancy. MRI of the spinal cord demonstrated a thoracic syringomyelia, a dysplastic conus medullaris, and an absence of coccyx and distal sacrum, called caudal regression syndrome or caudal agenesis. CONCLUSION: The caudal regression syndrome refers to sacral agenesis associated with spinal cord anomalies, e.g. syringomyelia. Sacral agenesis is marked by total absence of the coccyx and total or distal absence of the sacrum. An abnormal backside combined with a history of maternal diabetes mellitus in pregnancy is highly suggestive for the presence of caudal regression syndrome.     

Diabetes mellitus, exocrine pancreatic deficiency, hypertrichosis, hyperpigmentation, and chronic inflammation: confirmation of a syndrome

Abstract:  Type 1 diabetes mellitus is characterized by dysregulation of the immune system leading to inflammation and selective destruction of pancreatic beta cells. Mild to moderate pancreatic exocrine insufficiency is found in patients with type 1 diabetes. Diabetes mellitus may also be part of a syndrome occasionally involving hair and skin abnormalities. We report our observations on two siblings with insulin-dependent diabetes, severe exocrine pancreatic deficiency, pigmented hypertrichotic skin patches with induration and chronic inflammation. The first sibling presented at the age of 9 months with hypertrichosis and hyperpigmentation, particularly on her back and legs and then developed diabetes mellitus at the age of 4 yr. The second sibling presented with exactly the same clinical features but at a later age of 12 yr. Both siblings had severe pancreatic exocrine deficiency with chronic persistent inflammation. Some of the clinical features in these siblings resemble those described by Prendiville et al. although our patients had additional features. The chronic inflammatory response in both siblings is highly suggestive of some form of immune dysregulation. The presence of consanguinity in the parents and similarity of clinical features in the siblings are suggestive of a novel autoimmune disorder, possibly secondary to autosomal recessive inheritance.     

Pervasive developmental disorders not otherwise specified. A developmental-psychopathological approach for the development of made-to-measure treatment planning.

Diagnosis and classification of autism and related pervasive developmental disorders is both easy and difficult. Infantile autism is a characteristic syndrome on which many publications have appeared in the last 50 years. Conversely, the diagnosis and even the classification of children with pervasive developmental disorders related to autism is difficult. Although children with these disorders are twice as numerous as children with infantile autism, growing attention has been directed to at the latter group since the last decade. In this paper, autism and related disorders are described as a developmental disorder as well as a spectrum disorder. The spectrum of clinical symptoms can be explained, of which infantile autism is the most severe and prototypical manifestation. A working model is presented which accounts for all the problems of children with pervasive developmental disorders. An illustration of working with the model in practice is also given. The main lines of treatment and stages in treatment are briefly described.     

A new type of transient diabetes mellitus of infancy?

Two male siblings with transient diabetes mellitus were of normal birth weight, were asymptomatic, and did not require treatment with insulin. This may be a previously undescribed disorder or part of the range of transient diabetes mellitus of infancy. Previously reported infants with transient diabetes mellitus of infancy have usually been small for gestational age and have presented with glycosuric dehydration, infections, or growth failure. Insulin concentrations after oral glucose challenge showed inadequate insulin secretion with respect to the degree of hyperglycaemia in these children. Autosomal dominant inheritance may occur in some families with this disorder, and parents of some affected children may also have had asymptomatic or unrecognised transient diabetes mellitus of infancy. Leucocyte histocompatibility antigen typing of this family did not show any association of specific antigens with transient diabetes mellitus of infancy in the affected children.     

Office screening and early identification of children with autism

Autism spectrum disorders (ASDs), also called pervasive developmental disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revised), constitute a group of neurodevelopmental disorders that coalesce around a common theme of impairments in social functioning, communication abilities, and repetitive or rigid behaviors. The ASDs considered here include autism/autistic disorder, Asperger disorder/Asperger syndrome (AS), and pervasive developmental disorder not otherwise specified. This article focuses on autism/autistic disorder screening and its early identification, with a brief mention for AS screening, as there are limited tools and no recommendation for universal screening for AS.     

A new variant of a known mutation in two siblings with permanent neonatal diabetes mellitus

Permanent neonatal diabetes mellitus is a rare disorder usually presenting within the first few weeks or months of life. This disorder is genetically heterogeneous and has been associated with mutations in various genes. The genetic cause remains mostly unknown although several genes have been linked to this disorder. Mutations in KCNJ11, ABCC8, or INS are the cause of permanent neonatal diabetes mellitus in about 50%-60% of the patients. With genetic studies, we hope to increase our knowledge of neonatal diabetes, whereby new treatment models can become possible. Here, we defined a new variant of a known mutation, INS Exon 1-3 homozygous deletion, in two siblings diagnosed with permanent neonatal diabetes mellitus.     

Infantile-onset diabetes mellitus: a 1-year follow-up study

This study evaluates the clinical profiles and outcomes of children with infantile-onset diabetes mellitus (IODM) (onset at <1 year). Twelve infants with IODM presenting to our hospital from January 2003 to December 2007 are analyzed. All undergo thorough history, clinical examination, and investigations and are managed as per hospital-approved protocol and periodically followed up. Of 12 infants (3 boys and 9 girls), 9 have a family history of DM. The median age at onset is 2.5 months. Six infants have features suggestive of Wolcott-Rallison syndrome (WRS), 4 infants have type 1 DM, and 1 infant each has Fanconi-Bickel syndrome and maturity-onset diabetes of young. None have pancreatic agenesis or calculi. Human leukocyte antigen (HLA) typing shows DQ3 and DR15 alleles predominating. Two children with WRS died; the rest are being followed up. The incidence of IODM is increasing, with multiple syndromic associations rather than a single perspective.     

EEG and MRI findings and their relation with intellectual disability in pervasive developmental disorders

Background  The diagnostic category pervasive developmental disorders (PDDs) refer to a group of five disorders: autism, Rett syndrome, childhood disintegrative disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS). EEG abnormalities and seizures are considered much frequent in autistic subjects with comorbid intellectual disability (ID). In this study, we aimed to evaluate the EEG and MRI findings and their relation with ID in pervasive developmental disorder. Methods  A retrospective, cross-sectional and non-experimental study was performed. Subjects included 81 patients diagnosed with autism or PDD-NOS according to the DSM-IV criteria. The age range of the patients was 2–15 years (mean 6.6 years, SD 3.0). Among them, 21 (25.9%) were girls and 60 boys (74.1%). Results  Patients with severe ID had a higher rate of EEG abnormalities (P=0.03) than patients without ID as well as patients with mild or moderate ID. The association remained significant after the structural MRI abnormalities were controlled (P=0.04). The severity of ID was not associated with abnormal MRI. The most frequent EEG and MRI abnormalities were active epileptic anomaly/paroxysmal abnormality and cerebral atrophy/periventricular leukomalacia, respectively. Almost a third of the EEG abnormalities were associated with temporal cortex and adjacent cortical structures. Conclusions  Consistent with previous studies, almost a fourth of the patients in this relatively large sample of patients with pervasive developmental disorders had EEG and/or MRI abnormalities. EEG results indicate that temporal cortex may play a significant role in pervasive developmental disorders.     

Diabetes mellitus and profound insulin resistance in Johanson-Blizzard syndrome

Pancreatic exocrine insufficiency in Johanson-Blizzard syndrome (JBS) is well described but only two previous patient reports document pancreatic endocrine insufficiency manifested as diabetes mellitus, and each patient required only a modest dose of insulin to control hyperglycemia. We report a patient with JBS and new-onset diabetes mellitus with profound insulin resistance, with no clinical or laboratory evidence of pancreatic exocrine insufficiency.     

Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies

Forty patients with cystic fibrosis (CF), including 34 who died above age 10 years without having developed clinical diabetes mellitus and 6 who died with both cystic fibrosis and diabetes mellitus, were studied. The mean age of the female patients with CF but not diabetes was 15.8 +/- 5.6 years; of males without diabetes, 17.2 +/- 6.4 years; of female patients with CF and diabetes mellitus, 20.2 +/- 6.9 years; and of males with CF and diabetes, 21.3 +/- 6.6 years. The mean number of pancreatic islets in microscopic sections for patients with cystic fibrosis but not diabetes was 4.18 +/- 2.76/mm2, and the value for patients with both cystic fibrosis and diabetes mellitus was 2.61 +/- 2.07/mm2. The lowest density of pancreatic islets (1.69 +/- 0.48/mm2) for cystic fibrosis was found in patients with the latest-stage pathologic lesion. Nesidioblastosis (presence of ductuloinsular complexes) was identified in 14 of 38 cystic fibrosis patients, both with and without diabetes mellitus. The pancreatic islets of both diabetic and nondiabetic patients with CF showed hypertrophy; the mean volume of the three largest pancreatic islets for CF only was 0.0117 +/- 0.00657 mm3 and that for cystic fibrosis and diabetes was 0.00795 +/- 0.00599 mm3, both values being larger than normal. Ratios of the amounts of islet endocrine cells, A cells, B cells, and D cells, were determined by peroxidase--anti-peroxidase labeled antibody staining. The B cells composed 43.0% of endocrine cell mass in cystic fibrosis alone and 30.1% in cystic fibrosis with diabetes mellitus, which were lower than normal proportions. The D cell values, 11.9% in cystic fibrosis and 15.1% in cystic fibrosis with diabetes mellitus, on the other hand, were greater than normal ratios.     

Glucose intolerance and diabetes during cystic fibrosis

As a result of the improvement in life-expectancy in cystic fibrosis patients, simultaneous presence of cystic fibrosis and diabetes mellitus is no longer exceptional. In teenagers and young adults with cystic fibrosis, the prevalence of insulin-dependent diabetes mellitus (IDDM) is 7 to 10%. Fifty percent of cystic fibrosis patients have impaired glucose tolerance. These prevalences increase with advancing age. Insulin deficiency is a consistent feature. An endocrine pancreatic deficiency thus exists in addition to the exocrine pancreatic deficiency, as demonstrated by the fall in glucagon and pancreatic polypeptide productions. Development of insulin dependency is associated with deterioration in clinical status and indicates an adverse prognosis. Although in cystic fibrosis patients diabetes mellitus seems to occur as a result of different pathophysiologic mechanisms than those involved in autoimmune IDDM, the risk of degenerative complications is similar in both conditions. It follows that early detection of diabetes mellitus and appropriate insulin treatment are warranted in cystic fibrosis patients.     

La psychopathologie de l’enfant dyspraxique

The term “dyspraxia” was coined by Julian de Ajuriaguerra and Mira Stambak in 1964. This clinical term was treated very differently according to which explanatory model was adopted. Nowadays, it is used to refer to developmental coordination disorder in view of its neuro-developmental origin. In any case, the actual clinical situations vary and are often complex. In our opinion, it is first necessary to examine the differential diagnosis: apraxia in children caused by lesions, dysgraphia, simply delayed motor development, non-verbal learning disability syndrome, hemispheric specialisation deficits, pervasive developmental disorders (autisms, Asperger syndrome, atypical autism and other pervasive developmental disorders), mixed specific developmental disorders, multiple developmental disorder, and children with high potential. Next we focus on co-morbidity. Firstly, we look at psychopathological disorders associated with dyspraxia: autism and pervasive developmental disorders, dyscalculia/math disability, dyslexia/reading difficulties, dysphasia accompanied by verbal dyspraxia, intelligence deficiency, anxiety disorders, and attention-deficit hyperactivity disorder (ADHD). Secondly, we examine psychopathological disorders associated with dyspraxia. Children with developmental coordination disorder are less inclined to participate in collective games. As a result, there is a greater risk of them becoming lonely and isolated. They have higher child behaviour checklist (CBCL) scores in the somatic problems scale as well as for anxiety, depression and social withdrawal. They have low self-perception in sports as well as at school, which is related to their physical appearance and their self-esteem, attention deficit and externalized behaviour. These children are often at risk of academic failure and they suffer from oppositional defiant disorder and functional disorders. And finally, we believe that it is important to touch on the impact of these disorders on the family.     

Pancreatic Islets in Older Patients with Cystic Fibrosis with and without Diabetes Mellitus: Morphometric and Immunocytologic Studies

Forty patients with cystic fibrosis (CF), including 34 who died above age 10 years without having developed clinical diabetes mellitus and 6 who died with both cystic fibrosis and diabetes mellitus, were studied. The mean age of the female patients with CF but not diabetes was 15.8± 5.6 years; of males without diabetes, 17.2± 6.4 years; of female patients with CF and diabetes mellitus, 20.2± 6.9 years; and of males with CF and diabetes, 21.3± 6.6 years. The mean number of pancreatic islets in microscopic sections for patients with cystic fibrosis but not diabetes was 4.18± 2.76/mm², and the value for patients with both cystic fibrosis and diabetes mellitus was 2.61± 2.07/mm². The lowest density of pancreatic islets (1.69± 0.48/mm²) for cystic fibrosis was found in patients with the latest-stage pathologic lesion. Nesidioblastosis (presence of ductuloinsular complexes) was identified in 14 of 38 cystic fibrosis patients, both with and without diabetes mellitus. The pancreatic islets of both diabetic and nondiabetic patients with CF showed hypertrophy; the mean volume of the three largest pancreatic islets for CF only was 0.0117± 0.00657³ mm and that for cystic fibrosis and diabetes was 0.00795± 0.00599 mm³, both values being larger than normal. Ratios of the amounts of islet endocrine cells, A cells, B cells, and D cells, were determined by peroxidase-anti-peroxidase labeled antibody staining. The B cells composed 43.0% of endocrine cell mass in cystic fibrosis alone and 30.1% in cystic fibrosis with diabetes mellitus, which were lower than normal proportions. The D cell values, 11.9% in cystic fibrosis and 15.1% in cystic fibrosis with diabetes mellitus, on the other hand, were greater than normal ratios.     

Permanent neonatal diabetes with arthrogryposis multiplex congenita and neurogenic bladder – a new syndrome?

Abstract: Neonatal diabetes mellitus is a rare (1/400 000 newborns) but potentially devastating condition, which may be transient or permanent; typical symptoms occur within the first 4 wk of life. The transient form is a developmental insulin production disorder that resolves postnatally. Fifty to 60% of cases can be seen as transient form. Cases that require lifelong insulin therapy can be described as permanent condition. This fraction of cases is less common than the transient form. There are no clinical features that can predict whether a neonate with diabetes mellitus but no other dysmorphology will eventually have permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus. Some metabolic or genetic defects such as complete deficiency of glucokinase or heterozygous activating mutations of KCNJ11, encoding Kir6.2, were found in patients with PNDM. A preterm female infant with a gestational age of 36 wk was admitted to the neonatal intensive care unit in the first hours of life due to prematurity and intra‐uterine growth retardation. She was diagnosed as having arthrogryposis multiplex congenita on the first day. Hyperglycemia was detected on the third day of life, and she required insulin treatment. The patient is now 6 yr old with PNDM, arthrogryposis multiplex, neurogenic bladder, immune deficiency, constipation, and ichthyosis. Is this a new form of neonatal diabetes mellitus?