Science: Latest Developments

Children's Hospital Los Angeles is deeply appreciative of the philanthropic support to The Vision Center's research on optic nerve hypoplasia (ONH), an epidemic cause of pediatric visual impairment with lifelong central nervous system morbidity.

Contributions from our friends and donors enable Mark Borchert, MD, to lead a research team that is investigating the underlying causes of ONH in order to better diagnose, manage and ultimately prevent this devastating disease in children. We are proud to present this report, which details the research team's progress from this past year made possible through the kind generosity of our philanthropic partners.

Standing at the Forefront of ONH Research

Conducting rigorous research is crucial to The Vision Center's treatment framework. It provides physician-scientists with opportunities to gain a deeper understanding of diseases and develop new therapies that will improve outcomes for children here and around the world.

In the past year, Dr. Borchert has begun cross-disciplinary collaborations with colleagues in The Retinal Research Laboratory (part of The Vision Center), the Genomics Laboratory (part of the Department of Pathology and Laboratory Medicine) and the Department of Radiology at CHLA, as well as the Laboratory of Neuro-Imaging at the University of Southern California (USC), to pursue exciting new directions in ONH research.

1) Whole Exome Sequencing (WES)

Through a partnership with Laura Li, PhD, assistant professor of Clinical Pathology and co-director of the Genomics Lab at CHLA, Dr. Borchert is performing WES on children with ONH and their parents-the first research center to be using this type of comprehensive genetic testing on a cohort of children with this disease. WES has become an efficient and inexpensive means of identifying causative gene variants in neurodevelopmental and retinal diseases and offers the potential to identify causal genes and/or biological pathway alterations that contribute to ONH.

2) Pluripotent Stem Cells

In another genetic study of ONH, Dr. Borchert is collaborating with The Vision Center's David Cobrinik, MD, PhD, and Jennifer Aparicio, PhD, to grow retinal tissue in the Retinal Research Lab using induced pluripotent stem cells from children with ONH and from normal controls. The group is examining the retinal ganglion cells (the retinal cells that form the optic nerve) to see if there is a difference between the two groups. This could reveal if there is something unique in the genetic background of children with ONH that contributes to the pathology; however, a negative finding would be equally as important. If there is no difference between patient and control tissues, this could imply that genetics has nothing to do with the underdevelopment of the optic nerve, lending greater support to the theory that ONH may be caused by environmental exposures during fetal development.

3) Diffusion Tensor Imaging (DTI)

DTI is a method of magnetic resonance imaging (MRI) that maps the location and diffusion of water molecules in bodily tissues, giving researchers information about tissue structures on a microscopic level. Dr. Borchert is partnering with Marvin Nelson, MD, MBA, chair of the Department of Radiology at CHLA, and Yonggang Shi, PhD, assistant professor of Neurology at the Keck School of Medicine of USC, to use DTI brain scans to get a first-ever look at the full optic nerve pathway in children with ONH. So far, the group has scanned three children with unilateral ONH since this patient population offers an opportunity to compare the optic nerve track in the diseased eye with the normal eye. Preliminary data is currently being analyzed.

Recent Hydrocephalus and ONH Studies

ONH at Children's Hospital Los Angeles

Dr. Mark Borchert and The Vision Center at Children's Hospital Los Angeles have a website on all things ONH, including research updates, FAQs, a searchable database of resources in your area, and more. Visit


Title: Optic Nerve Hypoplasia Syndrome: A Review of the Epidemiology and Clinical Associations
Authors: Pamela Garcia-Filion, PhD, MPH, and Mark Borchert, MD
PubMed Central link:
Summary: Optic nerve hypoplasia (ONH) has developed into a leading cause of congenital blindness. The frequently associated features of hypopituitarism and absent septum pellucidum were felt to have embryonic linkage as "septo-optic dysplasia" or "de Morsier's syndrome." More recent studies have suggested these associations are independent of one another. This review provides an assessment of the historical and recent evidence linking neuroradiologic, endocrinologic and developmental morbidity in patients with ONH. The prenatal risk factors, heritability, and genetic mutations associated with ONH are described.

Title: Serum Prolactin Concentrations in Relation to Hypopituitarism and Obesity in Children with Optic Nerve Hypoplasia
Authors: Amy Vedin, Pamela Garcia-Filion, Cassandra Fink, Mark Borchert, Mitchell Geffner
PubMed Central link:
Summary: The majority of children with optic nerve hypoplasia (ONH) develop hypopituitarism and many also become obese. These associated conditions are a major cause of morbidity and are possibly due to hypothalamic dysfunction. Because mild hyperprolactinemia often occurs in subjects with disorders of the hypothalamus, we examined whether hyperprolactinemia was present in children with ONH during the first three years of life and whether it was a marker for hypopituitarism and/or obesity.

Title: Newborn thyroid-stimulating hormone in children with optic nerve hypoplasia: Associations with hypothyroidism and vision
Authors: Cassandra Fink, MPH, Amy M. Vedin, MD, Pamela Garcia-Filion, PhD, Nina S. Ma, MD, Mitchell E. Geffner, MD, and Mark Borchert, MD
PubMed Central link:
Summary: The purpose of this study was to assess in children with optic nerve hypoplasia (ONH) whether newborn screening (NBS) thyroid-stimulating hormone (TSH) measurements can detect central hypothyroidism and whether newborn TSH or subsequent thyroidal status is associated with visual function.

Press Releases

No Evidence to Support Stem Cell Therapy for Pediatric Optic Nerve Hypoplasia published in the Journal of the American Association for Pediatric Ophthalmology and Strabismus that accompanied a paper of ours that was published in that journal. The paper, documents the findings of a study we did into the effectiveness of stem cell therapies for the treatment of optic nerve hypoplasia.

Dr. Borchert’s Office Responds to Stem Cells China

From the ONH Research Program at Childrens Hospital Los Angeles:

The syndrome of optic nerve hypoplasia (ONH) is a congenital condition in which the optic nerves do not fully develop. ONH causes vision impairment and may also cause hormone deficiencies, developmental delay, and/or brain malformations. Some children carry the diagnosis of septo optic dysplasia (SOD) or DeMorsier syndrome but it is important to note that ONH, SOD, and DeMorsier are three different terms to describe the same condition. All children with ONH are at high risk for hypopituitarism (hormone problems), developmental delays, and midline brain malformations.

All children diagnosed with ONH need an MRI (picture of their brain) to look for any structural abnormalities. Some of the more common findings are a missing septum pellucidum, a small or absent corpus callosum, or pituitary gland abnormalities. Based on a prospective study of children with ONH, we know that the septum pellucidum is NOT associated with any adverse outcomes but a small or absent corpus callosum is associated with developmental delays. Although pituitary gland abnormalities on an MRI scan may signify hormone problems, even children with normal pituitary glands on MRI are at risk for hormone problems.

Hormone deficiencies are very common in children with ONH; in fact, more than 70% of children with ONH have some type of hormone problem. The pituitary gland, or "master gland" controls growth hormones, sex hormones, thirst and hunger responses, temperature, and more. It is strongly recommended that all children with ONH undergo a full endocrine work-up to determine their hormone status. All of the hormone deficiencies can be easily treated with replacement therapy in the form of medication.

Vision impairments in children with ONH ranges from completely blind with no light perception, to very good vision and it may occur in one or both eyes. Most children with ONH experience some improvement in their vision during their early childhood years. Vision impairment in ONH does not worsen.

Currently there is no cure for ONH. We are aware of the Stem Cells China program; however, we have not yet reached the state of knowledge with which stem cell treatment for ONH in humans can be done in the US or Europe. Research with stem cells for this and other optic nerve conditions is being done on laboratory animals. Stem cells research is the most promising form of therapy for ONH in the future; unfortunately, it is far from ready for use in humans. We have not yet even achieved success in treating mice with stem cells. There are considerable risks to this treatment as it is purportedly being administered in China, and the benefits are presently unknown. In the US and Europe experimental research on humans, such as that being conducted in China, is considered unethical. The testimony of previous recipients that stem cell therapy resulted in improved vision bears little scientific merit as most children with ONH enjoy late, spontaneous improvement in vision. Based on this information, we are unable to recommend the stem cells china program as a safe and effective treatment of ONH.

If you need more information, you may contact Cassandra Fink at 323-361-2267.

For more information please visit the following articles:

Children's Hospital St. Louis


Dr. Borchert NPR Article

ONH Paper Published in Journal of Pediatrics

We’ve been given permission to post a PDF of a 2006 Journal of Pediatrics paper on endocrine abnormalites related to ONH. Reprinted from The Journal of Pediatrics, Vol. 148, Ahmad, T, Garcia-Filion, P, Borchert, M, Kaufman F, Burkett, L, Geffner, M, Endocrinological and Auxological Abnormalities in Young  Children with Optic Nerve Hypoplasia: A Prospective Study, pages 78-84, Copyright 2006, with permission from Elsevier.

Journal of Pediatrics March 2008

ONH Guide for Parents Now Available in Spanish

Una descripción de diagnóstico general en español: Hipoplasia del Nervio Óptico: Guía Para Los Padres (PDF).

Translated from Optic Nerve Hypoplasia: A Guide for Parents (PDF), written by Dr. Francine Kaufman, Dr Neal Kaufman, Dr. Mark Borchert and Talia Inlender.

Research Initiatives

An update on hydrocephalus research initiatives at Chicago’s Children’s Memorial Hospital (PDF).

Optic Nerve Hypoplasia: Beyond Vision Problems

Beware of the Serious Medical and Developmental Complications

The clinical significance of optic nerve hypoplasia (ONH) has been misunderstood for decades owing to its association with “septo-optic dysplasia” in the medical literature. Recent studies have shed light on the risks for associated endocrinologic and developmental problems with ONH and raised questions about the rationale for considering “septo-optic dysplasia" as a distinct entity. Children with ONH frequently have global developmental delay, autistic behaviors, obesity, short stature and life-threatening endocrine deficiencies regardless of presenting symptoms and neuroradiographic findings.

Recently, in Sweden the prevalence of ONH was reported as 7/100,000 where it is the single leading cause of infant blindness. A more recent study from northern England reported a similar prevalence of 10/100,000. While the prevalence is currently unknown for North America, most pediatric ophthalmologists agree that its incidence is increasing, and that it is now a leading cause of blindness in young children, surpassing retinopathy of prematurity.

ONH is a neurodevelopmental abnormality that primarily affects vision and is significantly associated with a high prevalence of varying degrees of hypopituitarism, delayed neuropsychological development and other brain malformations. Unfortunately, sudden death (presumably due to occult hypopituitarism) also occurs in a number of ONH cases. Initial clinical findings currently have little prognostic value but research has suggested that early identification of associated abnormalities may improve outcomes. In consideration of the high prevalence of adverse outcomes and apparent rise in occurrence of ONH, it becomes crucial that pediatricians become aware of early signs of ONH, the necessary steps in managing a patient with ONH and the importance of close follow-up to monitor for developing endocrinopathies.

The earliest signs of ONH may present during the neonatal period and include jaundice and/or hypoglycemia. Nystagmus is present in a majority of bilateral cases and parents may express concern about their child ‘not looking at them’ or failing to focus on objects. Unilateral ONH may be more difficult to detect since visual impairment of the affected eye may be masked by the compensating vision of the normal eye. In such cases, strabismus or a weakly reactive pupil in one eye may be present to elicit concern. Suspicion of unilateral or bilateral ONH should be followed up with a referral to a pediatric ophthalmologist for diagnosis by fundus examination.

Every ONH case, whether unilateral or bilateral, should have endocrinologic evaluation and neuroradiographic imaging for associated abnormalities. A recent prospective cohort study published in the Journal of Pediatrics revealed that the high prevalence of endocrinopathies (72%) does not correlate with laterality of disease or neuroradiographic evidence of pituitary dysgenesis; thus it is important to examine each case with an assumption of high risk for hormonal dysfunction. An MRI is recommended as the current standard of care for all newly diagnosed cases of ONH since more than one-third of cases have visible brain lesions, but its clinical value is debatable since rarely is a treatable intracranial lesion found. Confirmation of “septo-optic dysplasia” has little prognostic value. In fact, numerous studies have reported the presence or absence of the septum pellucidum to be unrelated to any outcomes associated with ONH.

Endocrinologic evaluation, at a minimum, should include fasting morning cortisol and glucose levels, free T4 and TSH, and IGF-1 or IGF-BP3. Growth hormone deficit occurs in 64% of children with ONH, and may be an occult cause of hypoglycemia, even in the face of normal stature. Thus, if either IGF-1 or IGF-BP3 is low, or if there is growth deceleration, a growth hormone stimulation test should be performed. (A cortisol stimulation test can usually be performed simultaneously.) If the patient is less than 6 months of age, FSH and LH should also be obtained as this can be used to predict eventual delayed puberty. Beyond 6 months of age, sex hormones are too low to be of value. The risk for acquiring endocrine problems after previously normal hormone testing is unknown.

Vision is expected to improve to varying degrees until about the age of four years. The reason that vision improves at least slightly in most patients is unknown. Patching of one eye for possible superimposed amblyopia of the other eye (due to concomitant strabismus or refractive error) should only be instituted if the ONH (and presumed visual potential) is relatively symmetric. Although vision can improve in the worse eye of asymmetric ONH with patching, it rarely improves enough to be useful to the patient, and requires prolonged patching to maintain. This can be detrimental to the overall development of these children.

The diagnosis of ONH goes beyond visual impairment; it affects all aspects of child development. There is currently no rationale for categorizing “septo-optic dysplasia” as a separate entity from optic nerve hypoplasia, as absence of the septum pellucidum does not confer any apparent added risk for endocrinologic or developmental problems beyond those associated with optic nerve hypoplasia alone. All patients with ONH are at high risk for adverse outcomes associated with hypopituitarism, brain malformations and delayed neuropsychological development. Delayed diagnosis because of the mistaken notion that an infant “just has strabismus” can result in devastating consequences.

[An edited version of this article appears under the headline "Early detection of optic nerve hypoplasia may improve outcomes" in the May 2006 edition of AAP News. Reprinted with permission.]

Update: Neurosurgery

by Tadanori Tomita, MD
Neurosurgery Department Head
Children’s Memorial Chicago

The Children’s Memorial’s Division of Neurosurgery is deeply committed to providing comprehensive care for children with hydrocephalus and we value the partnership and inspiration that the One Small Voice Foundation offers through its dedication and enthusiasm.

Over the past year, with generous support from the Willie Fund and the One Small Voice Foundation, our team has initiated a study to examine the psycho-social impact of hydrocephalus on children and their families, with a goal of addressing the special needs and quality of life issues facing children at various stages of their lives.

As you know, the intellectual, social, cognitive and emotional impact of hydrocephalus can be considerable from a patient’s point of view. Yet there have been no studies to date that assess the health-related quality of life (HRQL) of these patients. Such a study will then allow hospitals and healthcare workers to cooperatively enhance the HRQL of patients with hydrocephalus and their families. Ultimately, data from this study will provide sound scientific evidence to help us advocate more effectively for further research that will lead to more successful treatments.

Since Children’s Memorial treats a large number of hydrocephalic patients, perhaps the largest number in the nation, this research is extremely important to improve the quality of life of children with hydrocephalus. Each year, we care for more than 1,500 children on an inpatient basis and record as many as 5,000 outpatient visits related to the ongoing management of hydrocephalus. In addition, the division annually performs between 500 and 600 hydrocephalus-related surgical procedures, including shunt placements and revisions. Over time, the results of this research could have tremendous significance for our clinical activities, allowing us to modify treatments and improve overall outcomes for patients with all forms of hydrocephalus.

The Division of Neurosurgery at Children's Memorial Hospital is proud to partner with the One Small Voice Foundation to improve treatment options and quality of life for children with hydrocephalus and we look forward to sharing the progress of this study with you.

Update: Optic Nerve Hypoplasia Research

by Cassandra Fink, MPH
Research Coordinator
Childrens Hospital Los Angeles

The Optic Nerve Hypoplasia (ONH) research study at Childrens Hospital Los Angeles (CHLA) has grown and developed in recent years. After much preparation, two new studies were approved and opened for enrollment within weeks of one another. In order to support this growth, we have expanded our research team from a two-man show to a team of three. In May, Cassandra Fink, MPH joined the team of Mark Borchert, MD and Pamela Garcia-Filion, MPH as the new Research Coordinator. Pamela has since become a Research Associate with the study and has begun analyzing data from the first 12 years of research.

Maternal prenatal questionnaires are among the first items on the list to be analyzed. One of the most common questions parents ask us is “What causes ONH?” Well, we are actively trying to answer that question and pinpoint the risk factors associated with ONH. One way we are doing this is by conducting a standard questionnaire with each of the mothers involved in our study at CHLA. This questionnaire asks about things that took place before and during pregnancy, like place of residence and eating habits. These questionnaires, unfortunately, only reach the families that are able to participate in our research at CHLA.

In order to obtain information from families all over the country, we have developed a national on-line survey. Our survey was posted on-line in February and we have seen an overwhelming amount of interest from families across the nation. This survey is completely confidential and no identifying information needs to be given in order to complete the survey. Once we reach our goal of 1500 completed surveys, we will look for any geographic or temporal patterns and conduct further in-depth questionnaires based on the findings from the surveys. Parents can find this survey on the following websites:;; and

Additionally, our study on early treatment of Growth Hormone (GH) deficiency in children with ONH was approved and seven subjects have been enrolled since January. We are very excited about this study and all our new developments and we are hopeful that the data from our studies will prove helpful in treating children with ONH and determining their future outcomes. We realize none of our research would be possible without the commitment and support of the families involved and we are grateful to them for allowing us to observe their children and for letting us into their lives.

Update: Hydrocephalus Research

by Dory Kranz
Executive Director
Hydrocephalus Association, San Francisco, CA

One Small Voice Foundation has encouraged and supported the Hydrocephalus Association to promote research into hydrocephalus. In the article that follows, I share with you three exciting ways in which the Association is supporting and advocating for better research into hydrocephalus.

We continue to learn from the Hydrocephalus Association Database Project, now in its third year. The goal of this project is to create a national registry to collect, store and synthesize information on the diagnosis, treatment, incidence and lifelong impact of hydrocephalus. The third phase of analysis was recently completed by Dr. Yvonne Wu, MD, MPH and her colleagues Nalin Gupta, MD and Margaret Wrensch, PhD at the Department of Neurology and Neurosurgery at the University of California, San Francisco (UCSF). Data from this set of 1,953 patients will be presented at the Annual Meeting of the American Association of Neurological Surgeons in San Francisco April 22-27, 2006. Slides from the previous year’s analysis, which was presented at the Pediatric Section Meeting of the AANS/CNS on December 10, 2004, are available on the Hydrocephalus Association website at

Highlights from that presentation include:

  • Nearly half the survey respondents have given written consent to be contacted for follow-up information or to be notified of a scientific study for which they might qualify as a participant.
  • Adult lifestyle outcomes such as working, having a driver’s license and being married are correlated with older age at diagnosis and fewer shunt revisions.
  • Issues of chronic headache (51%), having been treated for depression (43%) and substance abuse (9%) did not differ by age at diagnosis.

We are grateful to One Small Voice Foundation, Integra Foundation and Medtronic Foundation who made this database project possible and whose continued support will help us revise our questions and refine our analysis. We would like to acknowledge Cynthia Solomon, a founding member of the Hydrocephalus Association, for her vision and leadership on this project.

We had the pleasure and privilege of spearheading and helping to plan the first-ever National Institutes of Health (NIH)-sponsored workshop on hydrocephalus which took place in Bethesda, MD September 29-30, 2005. Over 150 neurosurgeons, neurologists, neuroscientists, patient advocates and NIH program staff joined together to dispel old myths, share new facts and decide on the most promising new directions for research. The moderators and presenters are now working together to write a manuscript sharing highlights of the presentations and outlining research priorities for hydrocephalus in the next five to ten years.

The Association also recently contracted with biostatisticians to compare the public health burden of hospitalizations for hydrocephalus between 1994 and 2004 with that of other conditions that are more well-known such as brain tumor, traumatic brain injury and childhood diabetes. We hope this information will be helpful in attracting media attention to hydrocephalus and in persuading congress to support more federal investment in hydrocephalus research through the National Institutes of Health (NIH), the Association for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control (CDC).

I hope you join with us in commending One Small Voice Foundation for supporting the Association so that we can carry out this important work.

The Surprises of Motherhood

Read this story (PDF) about one family’s journey through infertility, adoption and ONH. From the October 2004 issue of Adoptive Families magazine.