Fetal Description of the Pancreatic Agenesis and Holoprosencephaly Syndrome Associated to a Specific CNOT1 Variant.

Holoprosencephaly (HPE) is a clinically and genetically heterogeneous disease, which can be associated with various prenatal comorbidities not always detectable on prenatal ultrasound. We report on the case of a foetus carrying a semi-lobar HPE diagnosed at ultrasound, for which a fetal autopsy and a whole exome sequencing were performed following a medical termination of pregnancy. Neuropathological examination confirmed the semi-lobar HPE and general autopsy disclosed a total pancreas agenesis. Whole exome sequencing found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo in the foetus. The same variant was previously reported in 5 unrelated children. All individuals had HPE, and 4 out of 5 presented endo- and exocrine pancreatic insufficiency or total pancreas agenesis. CNOT1 encodes a subunit of the CCRN4-NOT complex, expressed at the early stage of embryonic development. This report is the first fetal description of the phenotype associating HPE and pancreatic agenesis linked to the recurrent CNOT1 missense c.1603C>T, p.(Arg535Cys). This finding strengthens the hypothesis of a specific recurrent variant associated with a particular phenotype of HPE and pancreas agenesis. The fetal autopsy that revealed the pancreas agenesis was crucial in guiding the genetic diagnosis and enabling accurate genetic counselling.

Pancreas and gallbladder agenesis in a newborn with semilobar holoprosencephaly, a case report.

BACKGROUND: Pancreatic agenesis is an extremely rare cause of neonatal diabetes mellitus and has enabled the discovery of several key transcription factors essential for normal pancreas and beta cell development. CASE PRESENTATION: We report a case of a Caucasian female with complete pancreatic agenesis occurring together with semilobar holoprosencephaly (HPE), a more common brain developmental disorder. Clinical findings were later confirmed by autopsy, which also identified agenesis of the gallbladder. Although the sequences of a selected set of genes related to pancreas agenesis or HPE were wild-type, the patient's phenotype suggests a genetic defect that emerges early in embryonic development of brain, gallbladder and pancreas. CONCLUSIONS: Developmental defects of the pancreas and brain can occur together. Identifying the genetic defect may identify a novel key regulator in beta cell development.

Dorsal pancreas agenesis, an incidental finding during acute appendicitis diagnosis; A case report.

INTRODUCTION AND IMPORTANCE: Dorsal pancreas agenesis is a rare congenital anomaly characterized by the absence or severe underdevelopment of the dorsal pancreatic bud. We report a case of a man who presented with features of appendicitis only to the incidentally discovery of dorsal pancreas agenesis during the diagnosis of acute appendicitis. We describe our experience on radiological diagnostic formulation and work up. CASE PRESENTATION: We present the case of a 45-year-old male patient who presented to the emergency department with symptoms and signs suggestive of acute appendicitis. A computed tomography scan and laboratory investigations confirmed the diagnosis of appendicitis. Incidentally, the scan also revealed the absence of dorsal pancreatic tissue, leading to the incidental diagnosis of dorsal pancreas agenesis. CLINICAL DISCUSSION: Dorsal pancreas agenesis is often asymptomatic and can be incidentally discovered during imaging studies or surgical interventions for unrelated conditions. In our case, the initial presentation of acute appendicitis provided an opportunity for the fortuitous diagnosis of dorsal pancreas agenesis. This emphasizes the importance of comprehensive imaging reporting in patients who undergo imaging for other conditions. CONCLUSION: This case report highlights the fortuitous discovery of dorsal pancreas agenesis during the diagnostic workup for acute appendicitis. It emphasizes the need for thorough imaging evaluation and reporting along with the importance of considering anatomical variations in patients presenting with abdominal symptoms. Increased awareness among healthcare professionals about such congenital anomalies can lead to their early recognition and appropriate management.

Agenesis of the Dorsal Pancreas: A Rare Cause of Diabetes and Recurrent Upper Abdominal Pain.

Agenesis of the dorsal pancreas is a rare congenital disorder with only a handful of cases described in the literature. It presents a diagnostic dilemma. Cross-sectional imaging is the cornerstone for diagnosis. It could have a syndromic association with polysplenia and cardiac anomalies. Pancreas divisum and chronic pancreatitis may present with similar symptoms and must be ruled out. We present a case of a 55-year-old male with recurrent non-specific abdominal pain and diabetes mellitus. He was managed with insulin and painkillers for symptomatic relief. We also reviewed approximately 68 cases described in the literature to date.

Congenital etiologies of exocrine pancreatic insufficiency.

Congenital exocrine pancreatic insufficiency is a rare condition. In a vast majority of patients, exocrine dysfunction occurs as part of a multisystemic disease, the most prevalent being cystic fibrosis and Shwachman-Bodian-Diamond syndrome. Recent fundamental studies have increased our understanding of the pathophysiology of these diseases. Exocrine pancreatic dysfunction should be considered in children with failure to thrive and fatty stools. Treatment is mainly supportive and consists of pancreatic enzyme replacement and liposoluble vitamins supplementation.

Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations.

CONTEXT: Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. OBJECTIVE: To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. SETTING: Twelve tertiary pediatric endocrine referral centers. PATIENTS: Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. MAIN OUTCOME MEASURES: Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. RESULTS: Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = -3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: -2.35, median BMI SDS: -0.52 SDS) with 20/29 (69%) cases having growth retardation. CONCLUSION: We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the pancreas-specific transcription factor 1A (PTF1A) enhancer and one with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, due to a KCNJ11 mutation. The two cases with mutations in the distal enhancer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analyses showed that these mutations can decrease expression of PTF1A which is involved in pancreas development. Both patients were born small for gestational age to consanguineous parents. Both were treated with insulin and pancreatic enzymes. One of these patients' fathers was also homozygous for the PTF1A mutation, whilst his partner and the parents of the other patient were heterozygous carriers. In the case with DEND sydrome, a previosly reported heterozygous KCNJ11 mutation, p.Cys166Tyr (c.497G>A), was identified. This patient was born to nonconsanguineous parents with normal birth weight. The majority of neonatal diabetes patients with KCNJ11 mutations will respond to sulphonylurea treatment. Therefore Glibenclamide, an oral antidiabetic of the sulphonylurea group, was started. This treatment regimen relatively improved blood glucose levels and neurological symptoms in the short term. Because we could not follow the patient in the long term, we are not able to draw conclusions about the efficacy of the treatment. Although neonatal diabetes mellitus can be diagnosed clinically, genetic analysis is important since it is a guide for the treatment and for prognosis.

Diabetes mellitus due to agenesis of the dorsal pancreas in a patient with heterotaxy syndrome.

Heterotaxy syndrome (HS) is a congenital disorder resulting from an abnormal arrangement of visceral organs across the normal left-right axis in the embryonic period. HS is usually associated with multiple anomalies, including defects of the major cardiovascular system and the extracardiovascular system such as intestinal malrotation, abnormal lung lobulation, bronchus anomalies, and pancreatic dysplasia. Although pancreatic dysplasia is occasionally accompanied with HS, the occurrence of diabetes mellitus (DM) due to pancreatic dysplasia in HS is rarely reported. We here report a case involving 13-year-old girl with DM caused by agenesis of the dorsal pancreas and HS diagnosed on the basis of the presence of a double-outlet right ventricle with bilateral pulmonary stenosis and intestinal malrotation with duodenal cyst. Timely diagnosis and treatment with insulin improved glycemic control.

Agenesia del páncreas dorsal: reporte de caso y revisión del tema / Agenesis of the dorsal pancreas: case report and topic review

Complete agenesis of the dorsal pancreas (ADP) is an exceedingly rare congenital anomaly, compatible with life. It may be asymptomatic and usually incidentally diagnosed. In symptomatic cases, the clinical manifestations vary from abdominal pain, pancreatitis and diabetes mellitus to exocrine insufficiency with steatorrhea. We present a case report of a 28 year old female with ADP, diagnosed incidentally during radiological evaluation for hyperglycemias in SARS COV2 concomitant affection. Magnetic resonance cholangiopancreatography confirmed the absence of, neck, body and tail of the pancreas. Knowing the pancreatic embryogenesis, the clinical presentation of their malformations and the main radiological characteristics is important for the proper diagnosis of these anomalies.

Coincidence of Polysplenia, Kartagener Syndrome, Dorsal Pancreas Agenesis, and Polycystic Kidney Disease in an Adult.

Here we present the case of an adult male patient with the anomalies of polysplenia, Kartagener syndrome, dorsal pancreas agenesis, and adult polycystic kidney disease. Familiarity with this extremely rare coincidence may improve diagnostic accuracy and patient management.

Dependent stomach sign and dependent intestine sign of dorsal pancreatic agenesis.

The 'dependent stomach sign' and 'dependent intestine sign' have been typically described for agenesis of dorsal pancreas. It is useful to differentiate pancreatic agenesis from the fatty infiltration of pancreas which is seen in pancreatic atrophy and pancreatic lipomatosis.

Diabetes mellitus due to agenesis of the dorsal pancreas in a patient with heterotaxy syndrome

Heterotaxy syndrome (HS) is a congenital disorder resulting from an abnormal arrangement of visceral organs across the normal left-right axis in the embryonic period. HS is usually associated with multiple anomalies, including defects of the major cardiovascular system and the extracardiovascular system such as intestinal malrotation, abnormal lung lobulation, bronchus anomalies, and pancreatic dysplasia. Although pancreatic dysplasia is occasionally accompanied with HS, the occurrence of diabetes mellitus (DM) due to pancreatic dysplasia in HS is rarely reported. We here report a case involving 13-year-old girl with DM caused by agenesis of the dorsal pancreas and HS diagnosed on the basis of the presence of a double-outlet right ventricle with bilateral pulmonary stenosis and intestinal malrotation with duodenal cyst. Timely diagnosis and treatment with insulin improved glycemic control.

Amyand's hernia in a child with permanent neonatal diabetes due to pancreatic agenesis.

Acute or perforated appendicitis within inguinal hernia is rarely encountered and it is known as Amyand's hernia. We report on the first case occurring in a 4-year-old boy affected by permanent neonatal diabetes mellitus due to pancreatic agenesis, an extremely rare condition. The initial suspicion of inguinal hernia was confirmed by ultrasound examination of the right inguinal region which revealed omental layers inside a swollen inguinal canal; this finding and the clinical presentation allowed a prompt and appropriate surgical management. The careful evaluation of this patient and early recognition of this unique presentation of appendicitis allowed trans-hernial appendectomy and immediate herniorrhaphy. Ultrasonography played a pivotal role to reach the correct diagnosis and to start a prompt treatment.

Heterotaxy syndrome: a case report / Síndrome heterotáxica: relato de caso

Heterotaxy syndrome is defined as an abnormal arrangement of some organs and vessels in association with dysmorphism. The authors describe the case of a patient with heterotaxy syndrome with poliesplenia incidentally diagnosed during imaging evaluation (computed tomography and small bowel barium study) of unrelated pathological condition.

Síndrome heterotáxica é definida como um arranjo anormal de alguns órgãos e vasos em associação a dismorfismo. Descrevemos o caso de uma paciente com síndrome heterotáxica diagnosticada incidentalmente durante avaliação por imagem (tomografia computadorizada e radiografia contrastada do intestino delgado) de condição patológica não relacionada.