Tag Archives: neonatology

Neonatology – Early Infantile Encephalopathy with Epilepsy (EIEE)

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in the lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases established 1983 by Abbey Meyers and others got Orphan Drug Act passed 1983.

Analysis: Early Infantile Encephalopathy with Epilepsy (EIEE) which has a prevalence of approximately 1 in 50,000 to 1 in 100,000.

The diagnosis of Early Infantile Encephalopathy with Epilepsy (EIEE) represents a diagnostic dilemma for the clinician as the symptoms overlap several other syndromes; some more amenable to treatment than others.

The presentation of epilepsy in combination with multiple other symptoms and as a component of many syndromes with or without encephalopathy represents a diagnostic dilemma.

There are multiple panels which are available to evaluate gene mutations including STXBP1 gene mutations which might provide a definitive diagnosis.

Epilepsy panels looking at 53 or 65 genes or larger panels studying 189 genes are often ordered to include the STXBPI gene which may have as many as 85 mutations to explain the multiple symptoms and variable severity.

Included in many of the panels are mutations which help diagnose:

  • West Syndrome
  • Lennox Gaustaut Syndrome
  • Dravet Syndrome
  • Rett Syndrome or Atypical Rett Syndrome
  • Ohtahara Syndrome

Treatable disorders often confused with STXBP1 mutations may include the following and others:

  • Pyridoxine-Dependent Epilepsy
  • Biotinidase Deficiency
  • Glucose Transporter 1 Deficiency
  • Holocarboxylase Synthetase Deficiency
  • Creatine Deficiency Syndromes
  • Serine Biosynthesis Disorders

Virtually all of the cases of STXBP1 have been sporadic with no family recurrence.

The possibility of gonadal mosaicism exists posing a very small risk for recurrence 

Neonatology – Chromosome Testing vs Exome Testing

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital                                                                                                       

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases was established in 1983 by Abbey Meyers and others.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background. With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

Background: There are over 500 conditions that have been implicated in Autism, Intellectual or Developmental Disabilities.

  • Routine Chromosome Studies will detect 3-5% of patients with Autism, Developmental Disabilities or Intellectual Disabilities
  • Fragile X testing is important especially in males (2-4% of males have Autism, Developmental Disabilities or Intellectual Disabilities 1-2% of females)
  • Other X Linked gene mutations
  • Rett Syndrome (X Linked in Girls) 0-4.4% – Average 1.5%: MECP2 gene, CDKL5 gene
  • Inborn Errors of Metabolism 1-5% cause Autism, Developmental Disabilities or Intellectual Disabilities

Exome Microarray:

  • 35% have a copy number variation (CNV’s)
  • 40% of CNV’s are new (de novo)
  • 14% of these patients have Autism, Developmental Disabilities or Intellectual Disabilities
  • 10% clear association with Autism, Developmental Disabilities or Intellectual Disabilities

14 major regions identified and correlated with Autism, Developmental Disabilities or Intellectual Disabilities.

Brain (Neuroimaging) 6-48% depending on severity of condition.

Other Causes: Prematurity, Spina Bifida, Cerebral Palsy, Infection.

If Chromosomal Microarray detects an unusual variant which is considered significant (up to 45 known at present):

  1. Approximately 20 are associated with heart problems
  2. Approximately 14 are associated with vision or hearing problems
  3. Approximately 6 are associated with seizures
  4. Approximately 5 are associated with kidney problems
  5. Approximately 2 are associated with blood disorder

What is the difference between chromosomal testing and exome testing?

  • The exome includes the protein coding genes
  • There are 23 pairs of chromosomes, 22 pairs of autosomes and 2 sex chromosomes. 2X’s in a normal female (usual female) and 1X and 1Y in a normal male (usual male)   

What is the Exome? The protein forming genes in an individual.

What is the Genome? Complete set of genes or genetic material in an individual.

Blood Leukocyte Karyotyping: Culture of circulating WBC’s in the blood of an individual, stopping the growth of the cells when they are dividing, exploding the cells and staining and matching the individual chromosomes. Examining the number, integrity and intactness of each chromosome, looking for an increased or decreased number and the gain or loss or exchange of chromosomal material. There are 22 pairs of autosomes, 1 from each parent, 2X chromosomes in the usual female and 1X and 1Y chromosome in the usual male.

*Chromosomal Microarray: Is evaluation of the components of the individual chromosomes, evaluating small additions or deletions of chromosomal material not identified by microscopic evaluation of chromosomes. Variations in the number of copies of DNA within a sequence are common and gains or losses may be associated with a disorder or increased or decreased susceptibility to a disorder e.g. CGG repeats in Fragile X. *First test considered for Autism, Developmental Disabilities or Intellectual Disabilities

Next Generation Sequencing (NGS): or High Throughput Sequencing: Term used to described several different types of sequencing DNA or RNA segments more quickly and economically. At the present time, is generally considered “experimental” in an individual.

 

Neonatology – Left Bronchopulmonary Sequestration with a Pleural Effusion

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background: A 35 year old female Gravida 2 Para 1 with one healthy child was referred by her OB/GYN for a fetal echocardiogram for a possible thickened myometrium at 22 weeks gestation.

Ultrasound showed a possible small echogenic mass in the lower left lung and a moderator band in the right ventricle which appeared “slightly higher in the right ventricle than is usually seen” giving the impression of a possible thickened myometrium.

The remainder of the fetal anatomical profile and fetal echocardiogram was within normal limits. Follow-up ultrasound was recommended in one month.

Case Study: The patient returned 5 weeks later at approximately 27 weeks gestation and ultrasound showed:

  • Large left pleural effusion
  • Deviation of the heart to the right lateral chest wall
  • Slight fetal ascites
  • Normal fetal movement
  • Fetal heart rate of 146 beats per minute
  • Fetal size 1 week 5 days greater than dates
  • Biophysical Profile was 8 of 8
  • Amniotic fluid volume was slightly increased.

The patient was referred to Pediatric Cardiology and Maternal Fetal Medicine the same day. The following findings were found:

  • An echogenic, homogeneous mass in the left lower lung, measuring 3.4×2.8×2.6 cm with a large feeder vessel with arterial flow was seen on Doppler and color scan.
  • Large left pleural effusion with mediastinal shift

Pediatric Cardiology evaluation confirmed a normal heart with normal cardiac function.

MRI was performed which confirmed a left bronchopulmonary sequestration with a large pleural effusion.

Seven days post initial diagnosis a left rocket thoraco-amniotic shunt was performed with good resolution of the left pleural effusion and only a slight mediastinal shift.

Weekly ultrasound studies with biophysical profiles were performed to monitor the patency of the shunt and fetal well being. At 37 2/7 weeks gestation, induction of labor was began with a Cook balloon for cervical ripening followed by oxytoin stimulation, artificial rupture of membranes and spontaneous delivery of a vigorous female infant, 2950 g, Apgar 8→9 after approximately a 4 hour labor. The thoraco-amniotic shunt was removed.

The pulmonary mass was less obvious on imaging studies and the feeding vessel was not seen. The infant continues to do well and will be followed to decide whether surgical intervention will be required.

Analysis: Rarely, a solid or cystic lung mass is found on routine fetal ultrasound – Congenital Cystic Adenomatoid Malformation (CCAM). 

CCAM is the most common fetal lung mass, sometimes called Congenital Pulmonary Adenomatoid Malformation (CPAM). These are usually:

  • Microcystic with small cysts measuring less than 5 mm each
  • Macrocystic with cysts measuring greater than 5 mm

The cysts may change in size over time and often resolve by term.

Occasionally polyhydramnios (too much amniotic fluid) and/or pleural effusions (fluid in chest cavity) may be present which can displace the position of the heart.

Usually these patients can be monitored with serial ultrasound (every 4-6 weeks) and fetal intervention is not required.

Occasionally due to increasing lung fluid accumulation with decreased cardiac function, fetal surgery with cyst drainage or thoraco-amniotic sac shunting may be required.

Neonatal surgery may be required and resection of the abnormal and non-functioning lung tissue is recommended because of an increased risk for infection.

BrochoPulmomary Sequestration (BPS) is the second most common fetal lung mass. In these cases, the often echogenic lung tissue does not connect to the tracheobronchial tree and commonly gets it’s blood supply from a source other than the pulmonary arteries, often directly from the aorta. They may have a cystic component and a combination Bronchopulmonary Sequestration (BPS) and Congenital Cystic Adenomatoid Malformation (CCAM) can occur.

Hydrothrorax can occur and in-utero shunting may be required as in the case presented.

Serial ultrasound studies with biophysical profile of the fetus should be done and include:

  • Amniotic fluid volumes (amniotic fluid indices)
  • Placental and cord Doppler studies
  • Non stress testing when appropriate

Despite the startling finding on ultrasound and the family trauma of dealing with the required close fetal surveillance and occasional fetal or neonatal intervention, fetal prognosis is usually quite good.

The prevalence of CCAM and BPS is not known but is approximately 3-9 per 10,000 births for CCAM and approximately 1 in 10,000 to 30,000 births for BPS.

The intralobular type is more common (70-85%) but usually presents later in childhood.

The extralobar type is more common in newborns (60%) and may be more common in males. The extralobular type can be intrathoracic or subdiaphragmatic and may be associated with diaphragmatic hernia, congenital heart disease, with or without other pulmonary abnormalities.

Both lesions have a small risk for malignant transformation which is estimated to be less than 1% with CCAM having a greater risk than BPS. 

Neonatology – Agenesis of the Corpus Callosum (ACC)

© 2018, GENASSIST, Inc.    

By Keith S. Wexler, MBA, CFO, Business Development Director, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Agenesis of the Corpus Callosum (ACC) is when the corpus callosum that connects both hemispheres of the brain in a fetus only partially develops or does not develop (agenesis) in pregnancy.

Agenesis of the Corpus Callosum Symptoms:

  • Low muscle tone
  • Vision and hearing difficulties
  • Variable developmental delay
  • Swallowing and feeding difficulties
  • Occasional seizures

Incidence: 1-7 per 1000 births

Agenesis of the Corpus Callosum can be inherited in an autosomal recessive manner, X linked dominant inheritance or be due to a new mutation in the fetus or can also be attributed to an infection or excessive alcohol consumption in pregnancy.

Autosomal recessive diseases are due to a child inheriting one deleterious gene from each parent. That couple’s recurrence risk for another child with Agenesis of the Corpus Callosum could approach 25% (1 in 4).

X linked dominant inheritance is due to the inheritance of one deleterious gene on one X chromosome from an affected parent, or can be due to a new mutation (de novo).

Several gene mutations have been implicated in the disorder:

  • Mutation in the SLC12A6 gene on the short arm of chromosome #15 (15q13-14)
  • ARX gene on the short arm of the X chromosome (Xp22.13)
  • SZT2 mutations on the short arm of chromosome #1 (1p34.2) and may be associated with seizures
  • DCC mutations on the long arm of chromosome #18 (18q21.3)

Several genetic companies are offering panels for mutational analysis for children with Agenesis of the Corpus Callosum.

Most Pediatric Neurologists are aware of this testing. However, not all cases will be diagnosed by these genetic tests.

 

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