Role of the DDX11 DNA Helicase in Warsaw Breakage Syndrome Etiology.

Warsaw breakage syndrome (WABS) is a genetic disorder characterized by sister chromatid cohesion defects, growth retardation, microcephaly, hearing loss and other variable clinical manifestations. WABS is due to biallelic mutations of the gene coding for the super-family 2 DNA helicase DDX11/ChlR1, orthologous to the yeast chromosome loss protein 1 (Chl1). WABS is classified in the group of "cohesinopathies", rare hereditary diseases that are caused by mutations in genes coding for subunits of the cohesin complex or protein factors having regulatory roles in the sister chromatid cohesion process. In fact, among the cohesion regulators, an important player is DDX11, which is believed to be important for the functional coupling of DNA synthesis and cohesion establishment at the replication forks. Here, we will review what is known about the molecular and cellular functions of human DDX11 and its role in WABS etiopathogenesis, even in light of recent findings on the role of cohesin and its regulator network in promoting chromatin loop formation and regulating chromatin spatial organization.

Animal Model Contributions to Congenital Metabolic Disease.

Genetic model systems allow researchers to probe and decipher aspects of human disease, and animal models of disease are frequently specifically engineered and have been identified serendipitously as well. Animal models are useful for probing the etiology and pathophysiology of disease and are critical for effective discovery and development of novel therapeutics for rare diseases. Here we review the impact of animal model organism research in three examples of congenital metabolic disorders to highlight distinct advantages of model system research. First, we discuss phenylketonuria research where a wide variety of research fields and models came together to make impressive progress and where a nearly ideal mouse model has been central to therapeutic advancements. Second, we review advancements in Lesch-Nyhan syndrome research to illustrate the role of models that do not perfectly recapitulate human disease as well as the need for multiple models of the same disease to fully investigate human disease aspects. Finally, we highlight research on the GM2 gangliosidoses Tay-Sachs and Sandhoff disease to illustrate the important role of both engineered traditional laboratory animal models and serendipitously identified atypical models in congenital metabolic disorder research. We close with perspectives for the future for animal model research in congenital metabolic disorders.

Congenital diabetes mellitus.

Congenital diabetes mellitus is a rare disorder characterized by hyperglycemia that occurs shortly after birth. We define "Diabetes of Infancy" if hyperglycemia onset before 6 months of life. From the clinical point of view, we distinguish two main types of diabetes of infancy: transient (TNDM), which remits spontaneously, and permanent (PNDM), which requires lifelong treatment. TNDM may relapse later in life. About 50% of cases are transient (TNDM) and 50% permanent. Clinical manifestations include severe intrauterine growth retardation, hyperglycemia and dehydration. A wide range of different associated clinical signs including facial dysmorphism, deafness and neurological, cardiac, kidney or urinary tract anomalies are reported. Developmental delay and learning difficulties may also be observed. In this paper we review all the causes of congenital diabetes and all genes and syndromes involved in this pathology. The discovery of the pathogenesis of most forms of congenital diabetes has made it possible to adapt the therapy to the diagnosis and in the forms of alteration of the potassium channels of the pancreatic Beta cells the switch from insulin to glibenclamide per os has greatly improved the quality of life. Congenital diabetes, although it is a very rare form, has been at the must of research in recent years especially for pathogenesis and pharmacogenetics. The most striking difference compared to the more frequent autoimmune diabetes in children (type 1 diabetes) is the possibility of treatment with hypoglycemic agents and the apparent lower frequency of chronic complications.

A Missing Flexor Hallucis Longus Muscle and Tendon in a Young Female Patient: A Case Report of a Rare Anomaly.

Anatomic variations of the long flexor tendons of the foot are not common. Tendinous bands connecting the flexor hallucis longus and the flexor digitorum longus are well known and have even been classified. Although the congenital absence of the flexor pollicis longus in the hand is well known, we found no reports of the absence of the flexor hallucis longus in the foot. We describe the case of a 32-year-old female who stepped on a crystal ashtray and transected the flexor hallucis tendon arising from the flexor digitorum longus. During surgery, the absence of the proper flexor hallucis longus muscle and tendon became apparent. This anomaly appears to be extremely rare, and its clinical importance is unknown, although our patient reported no functional problems before the accident.

Congenital Sialolipoma in an Infant.

Sialolipoma is a newly recognized tumor of the major and minor salivary glands and represents only 0.3% of all salivary gland tumors. Only 3 cases of congenital sialolipoma are available in the literature. In the current case, we performed a total parotidectomy with facial nerve preservation on a 12-week-old infant exhibiting huge mass in the parotid region. Histopathology results showed sialolipoma. There was no recurrence at the 18-month follow-up. Although it is a very rare disease in infants, congenital sialolipoma should be kept in mind in patients with parotid mass. The primary treatment is parotidectomy with facial nerve preservation.

Health-related quality of life for children with rare diagnoses, their parents' satisfaction with life and the association between the two.

PURPOSE: To examine children's health-related quality of life and parents' satisfaction with life and explore the association between the two in families where a child has a rare disorder. METHODS: We used a cross-sectional study design. A questionnaire was sent to parents of 439 school children (6-18 years) with congenital rare disorders. Children's health-related quality of life (HRQOL) was examined by Pediatric Quality of Life InventoryTM 4.0 (PedsQL) Norwegian version. Satisfaction with life was examined by Satisfaction with Life Scale (SWLS). RESULTS: The response rate was 48% (n = 209). The average age of the children was 12 years and 50% were girls. The parents scored their children with reduced physical, emotional, social and school functioning. The reductions were greatest in the physical area. Parents scored average to high on SWLS but significantly lower than the general Norwegian population. There was a positive association between parental SWLS and the children's social functioning and school functioning. CONCLUSION: Children with congenital, rare disorders often require assistance from many parts of the public service system. Caring for their physical needs should not conflict with their educational and social needs. It is important that the children's school-life is organized so that the diagnosis does not interfere with the children's education and social life more than necessary.

Familial progressive hypermelanosis in Indian monozygotic twins.

Familial hyperpigmentation, or melanosis universalis hereditaria, is a rare hyperpigmentary disorder with onset in infancy. Here, we describe monozygotic twins with similar pattern of progressive hyperpigmentation with onset in early neonatal period without any family history. Histopathological examination showed increased melanin throughout the epidermis. Although hereditary defects may influence melanogenesis resulting in a pigmentary anomaly, the pathogenesis of hyperpigmentation in this case remains unclear.

A case of congenital partial absence of the left pericardium presenting with atypical chest pain.

Congenital absence of the pericardium (CAP) is a rare cardiac malformation and can be defined as the partial or total absence of the fibroelastic sac that surrounds the heart and great vessels. As the patients are often asymptomatic or have nonspecific symptoms, the diagnosis of this rare congenital anomaly is difficult. Therefore, it is usually diagnosed incidentally during imaging, intraoperatively, or during postmortem examinations. In this regard, it is important to keep specific images in mind during the examination and to suspect CAP to make an accurate diagnosis. In this report, we present a case of a 42-year-old male who presented with a complaint of atypical chest pain and was diagnosed with CAP using multimodality imaging.

Portal annular pancreas. A rare variant and a new classification.

CONTEXT: Portal annular pancreas is a rare congenital anomaly resulting from fusion of the pancreatic parenchyma around the portal vein/superior mesenteric vein. It is asymptomatic, but could have serious consequences during pancreatic surgery, if unrecognized. We describe a variant of this anomaly encountered during pancreaticoduodenectomy and propose a new classification. CASE REPORT: We report a 51-year-old male who underwent a pancreaticoduodenectomy for periampullary carcinoma. After division of the pancreatic neck, a sheath of tissue was found posterior and extending to the left of the portal vein. When we divided this tissue, a large duct was encountered; this duct communicated with the main pancreatic duct. On review of the CT images, the main pancreatic duct was seen to be passing posterior to the portal vein and a smaller accessory pancreatic duct was present anterior to the portal vein. We describe the surgical implications. CONCLUSION: This variant of portal annular pancreas has not yet been reported during pancreaticoduodenectomy and we propose a new classification for this fusion anomaly.

Population-based surveillance for rare congenital and inherited disorders: models and challenges.

Worldwide, an estimated 7.9 million children are affected by congenital and inherited disorders. Some disorders are relatively common, affecting tens of thousands of newborns annually; others are rare, involving disorders that, in extreme cases, can affect less than 30 infants per year. However, this infrequency does not reduce the impact or burden on individuals and their families. Congenital defects can cause long-term disability, have a lifelong impact on health, and cost billions of dollars in care. Collection of population-based surveillance data ideally enables the discovery of etiologies for rare congenital disorders of unknown cause, allows for examining outcomes, and evaluating treatments and interventions for children with all types of congenital and inherited disorders. Many challenges are associated with performing population-based surveillance, such as difficulty in ascertaining appropriate diagnoses and frequent unavailability of necessary resources. This chapter focuses on the importance of population-based data and uses national and international surveillance systems as models for how these rare disorders can be better understood.

Granulomatous uveitis and congenital cataract: a rare association.

INTRODUCTION: The association of a granulomatous uveitis and congenital cataract and is rarely observed in newborn children. We describe the history of two patients presenting simultaneously with these two features in the absence of a TORCH infection. PATIENTS AND METHODS: The first patient, a boy born in 1997, presented to our hospital two days after birth with multiples Koeppe's and Busacca's nodules and bilateral cataract. The second patient, a boy born in 2006, was referred two weeks after birth. He presented with a severe unilateral granulomatous uveitis, multiples iris nodules, a high intraocular pressure of 45 mmHg and a congenital cataract. THERAPY AND OUTCOME: Lens extraction produced a rapid resolution of uveitis in these two patients. TORCH infection was ruled out in both children by history, extensive serologies performed simultaneously in mother and child or PCR of ocular fluids. CONCLUSIONS: A congenital cataract associated with a granulomatous uveitis is an extremely rare association. The removal of the lens resulted in complete resolution of the inflammation: a phacogenic mechanism could be at the origin of ocular inflammation in both cases.

Undiagnosed and Rare Diseases in Perinatal Medicine: Lessons in Context and Cognitive Diagnostic Error.

Critically ill neonates experience high rates of morbidity and mortality. Major diagnostic errors are identified in up to 20% of autopsied neonatal intensive care unit deaths. Neonates with undiagnosed or rare congenital disorders may mimic critically ill neonates with more common acquired conditions. The context of the diagnostic evaluation can introduce unique biases that increase the likelihood of diagnostic error. Herein is presented a framework for understanding diagnostic errors in perinatal medicine, and individual, team, and systems-based solutions for improving diagnosis learned through the implementation and administration of an undiagnosed and rare disease program.

Autoinflammatory Disorders with Perinatal Onset.

Autoinflammatory disorders are rare genetic defects that result in inflammation in the absence of an infectious or autoimmune disease. Although very rare, these disorders can occur in the perinatal period, and recognizing their presentation is important because there are often long-term complications and effective targeted therapies for these disorders. Most of these disorders present with rash, fevers, and laboratory evidence of inflammation. Importantly, these disorders can now be separated into their pathophysiologic mechanisms of action, which can also guide therapies. The article reviews the different mechanisms of autoinflammatory disorders and highlights those disorders that can present in the newborn period.

Mitochondrial DNA Depletion Syndromes.

Mitochondrial disorders present in a myriad of ways, which causes them to be included in the differential diagnosis for many patients with undiagnosed disease. A subset of mitochondrial disorders are caused by intrinsic defects in the mitochondrial replication machinery, leading to loss of cellular mitochondrial content over time. The diagnosis of mitochondrial disease is complex. Several best-practice guides are available that enable a higher likelihood of detecting a mitochondrial disorder. The application of genomic sequencing and advanced physiologic analysis of the electron transport chain can offer more definitive evidence of mitochondrial dysfunction.

Nonimmune Anemias.

Anemia in the newborn period can be a diagnostic challenge. This article explores the diagnosis, work-up, and differential diagnosis of anemia in this patient population with a focus on anemia that is not related to blood loss or immune-mediated conditions (isoimmune hemolysis).

Rare Vesiculopustular Eruptions of the Neonatal Period.

Numerous disorders present with vesiculopustular eruptions in the neonatal period, ranging from benign to life-threatening. Accurate and prompt diagnosis is imperative to avoid unnecessary testing and treatment for benign eruptions, while allowing for adequate treatment of potentially fatal disorders. In this review, we highlight several rare blistering diseases of the newborn. A diagnostic approach is outlined to provide clinicians with a framework for approaching a neonate with vesicles, pustules, or ulcers.

Neonatal and Infant Appendicitis.

Neonatal appendicitis is a rare disease with a high mortality rate. Appendicitis is difficult to diagnose in neonatal and infant populations because it mimics other more common conditions in these age groups. Furthermore, signs and symptoms of appendicitis are often nonspecific in nonverbal patients and a high index of suspicion is necessary to initiate the appropriate diagnostic work-up. The keys to successful management of appendicitis in infants include keeping the diagnosis on the differential in the setting of unexplained intra-abdominal sepsis, following a diagnostic algorithm in the work-up of infant abdominal pathology, and performing appendectomy once the diagnosis is confirmed.

Neonatal Acute Liver Failure.

Neonatal acute liver failure (NALF) is a rare disease with a few known primary causes: gestational alloimmune liver disease (GALD), viral infections, metabolic diseases, and ischemic injury. Many cases still do not have a known cause. Laboratory evaluation may suggest a diagnosis. Most of the known causes have disease-specific treatments that improve outcomes. Survival is improving with better knowledge about and treatment options for GALD; however, overall mortality for NALF is still 24%. Liver transplant remains an important option for neonates with an indeterminate cause of NALF and those who do not respond to established treatments.

Presentation and Management Patterns of Lower Urinary Tract Symptoms in Adults Due to Rare Inherited Neuromuscular Diseases.

OBJECTIVE: To describe the urologic sequalae of several rare congenital neuromuscular diseases. METHODS: We retrospectively reviewed medical records at Gillette Specialty Healthcare (2014-2018) of patients presenting to urology clinic with lower urinary tract symptoms and select rare congenital diseases: muscular dystrophy, spinal muscular atrophy, and Rett syndrome. RESULTS: Muscular dystrophies (n = 19) are X-linked myogenic disorders characterized by progressive muscle wasting and weakness. Men present to the urologist at variable ages, typically with complaints of functional incontinence and normal cystometrograms; we manage them with oral anticholinergic medications, condom catheter, or suprapubic catheter. Spinal muscular atrophy (n = 6) is a rare autosomal recessive disease characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem leading to progressive muscle weakness and atrophy. Patients typically present with nephrolithiasis and urinary retention in late adolescence/early adulthood, but timing varies. Filling cystometrograms have been normal. We allow passive retention with intermittent catheterization and creation of catheterizable channels, when indicated. Rett syndrome (n = 5) is a rare, noninheritable genetic condition affecting females characterized by a brief period of normal development followed by loss of speech and purposeful hand use; there are characteristic behaviors. Patients present in early adulthood with complaints of urinary retention. We manage retention with permissive retention or sphincter chemodenervation. CONCLUSION: Several congenital neuromuscular conditions can cause lower urinary tract symptoms when these individuals become adults. We have discussed the clinical characteristics and management of select neurogenic and myogenic bladder conditions seen in adults with congenital conditions.

Congenital Diarrheal Syndromes.

Congenital diarrheal disorders are heterogeneous conditions characterized by diarrhea with onset in the first years of life. They range from simple temporary conditions, such as cow's milk protein intolerance to irreversible complications, such as microvillous inclusion disease with significant morbidity and mortality. Advances in genomic medicine have improved our understanding of these disorders, leading to an ever-increasing list of identified causative genes. The diagnostic approach to these conditions consists of establishing the presence of diarrhea by detailed review of the history, followed by characterizing the composition of the diarrhea, the response to fasting, and with further specialized testing.