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Original Investigation | Clinical Sciences

Incidence and Associated Endocrine and Neurologic Abnormalities of Optic Nerve Hypoplasia FREE

Brian G. Mohney, MD1; Ryan C. Young, MD2; Nancy Diehl, BS3
[+] Author Affiliations
1Department of Ophthalmology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
2College of Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
3Division of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
JAMA Ophthalmol. 2013;131(7):898-902. doi:10.1001/jamaophthalmol.2013.65.
Text Size: A A A
Published online

Importance  Optic nerve hypoplasia (ONH) is an increasingly recognized cause of congenital blindness in children; however, there is significant discord regarding its incidence and the rate of associated conditions.

Objective  To determine the incidence of ONH and the rate of associated endocrine, neurologic, and developmental abnormalities among a population-based cohort of pediatric patients.

Design  Retrospective, population-based study.

Setting  Olmsted County, Minnesota (95.7% white in 1990).

Participants  All pediatric residents (aged <19 years) of Olmstead County, diagnosed as having ONH from January 1, 1984, through December 31, 2008.

Main Outcomes and Measures  Incidence of ONH and the rate of associated endocrine, neurologic, and developmental abnormalities.

Results  Optic nerve hypoplasia was diagnosed in 19 pediatric patients during the 25-year study period, for an annual incidence of 2.4 (95% CI, 1.2-3.5) per 100 000 residents younger than 19 years or 1 in 2287 live births. The mean age at diagnosis was 2.1 years, and 10 (53%) patients were male. Commonly associated perinatal conditions included primiparity in 8 patients (42%), premature birth in 6 (32%), and maternal diabetes mellitus in 3 (16%). Of the 19 study patients, 16 (84%) had bilateral involvement at initial examination, 9 (47%) had decreased visual acuity, 8 (42%) had strabismus, and 5 (26%) had nystagmus. Systemic conditions included developmental delay in 12 (63%), neurologic deficits in 10 (53%), and endocrine dysfunction in 5 (26%).

Conclusions and Relevance  This population-based study demonstrated an incidence of ONH of 1 in 2287 live births. More than half of the patients had developmental and neurologic deficits, and one-fourth had a diagnosis of endocrine dysfunction.

Optic nerve hypoplasia (ONH) is one of the leading causes of childhood blindness and visual impairment in the United States.1 It is a nonprogressive congenital disease characterized histologically by a subnormal number of optic nerve axons in the optic nerve tracts resulting in small, pale optic discs.2 Optic nerve hypoplasia often occurs in association with a number of clinically important endocrine and central nervous system abnormalities as part of a spectrum of diseases known as septo-optic dysplasia, a congenital syndrome involving developmental abnormalities of the optic nerves, midline brain structures, and cerebral hemispheres.3,4 Developmental delays are a common occurrence in children with ONH as well and encompass a wide spectrum from mild communication delays to profound motor and global delays.5

Optic nerve hypoplasia has been an increasingly recognized cause of congenital blindness in children during the past 30 years. In 1981, Acers3 estimated the incidence of ONH to be 2 per 100 000 residents. More recently, the incidence of ONH in Sweden has been estimated at 6.3 per 100 000,6 and incidence estimates in England had risen to 10.9 per 100 000 in 2006.7 However, there are no known incidence reports of ONH in North America. The purpose of this study was to determine, using a medical record retrieval system, the incidence and associated endocrine and neurologic abnormalities observed in a population-based cohort of patients younger than 19 years with a diagnosis of ONH.

Medical records were retrospectively reviewed for all pediatric patients (aged <19 years) living in Olmsted County, Minnesota, when diagnosed as having ONH from January 1, 1984, through December 31, 2008. Potential cases of ONH were identified by using the resources of the Rochester Epidemiology Project, a medical record linkage system designed to capture data on any patient-physician encounter in Olmsted County.8 The racial distribution of Olmsted County residents in 1990 was 95.7% white, 3.0% Asian American, 0.7% African American, and 0.3% Native American. In 2000 in Olmsted County, 91.1% of adult residents had a high school diploma or higher degree (vs 80.4% nationally), 34.7% (vs 24.4% nationally) had a bachelor’s degree or higher, the mean annual household income was $51 000 (vs $42 000 nationally), and 3.8% of families (vs 9.2% nationally) were below the poverty level.9 The population of this county (106 470 in 1990) is relatively isolated from other urban areas, and virtually all medical care is provided to residents by Mayo Clinic or Olmsted Medical Group and affiliated hospitals.

This study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Group. Medical records were reviewed for all patients younger than 19 years who were diagnosed as having ONH, septo-optic dysplasia, or DeMorsier syndrome during the 25-year study period. Optic nerve hypoplasia was defined as an abnormally small optic nerve, as determined by the examining physician. Incident cases included only those patients who had an initial diagnosis of ONH during the study period and were living in Olmsted County at the time. All diagnoses are carefully entered into the Rochester Epidemiology Project database, and residency status was verified by specially trained personnel. The complete medical records for all incident cases were abstracted by the medical student investigator (R.C.Y.) to include information on demographics, prenatal risk factors, initial visit information, diagnoses, and follow-up visit information. Each diagnosis was confirmed by a pediatric ophthalmologist (B.G.M.), who reviewed the medical record. Patients not living in Olmsted County at the time of diagnosis were excluded.

The incidence and prevalence of ONH was estimated by using the age- and sex-specific population figures from Olmsted County, Minnesota. Yearly incidence rates for each age and sex group were determined by dividing the number of incident cases within their respective group by the estimated total Olmsted County resident population of the group for that given year. Population figures for 1990 and 2000 were obtained from the United States census data, and population figures for the intercensus years were estimated by using a linear interpolation.

Nineteen cases of ONH in pediatric patients were identified during the 25-year study period, for an annual incidence of 2.4 (95% CI, 1.2-3.5) per 100 000 residents younger than 19 years or 1 in 2287 live births. The incidence during the first 5 years of the study (1984-1988) was 1.52 per 100 000 (95% CI, 0.00-3.25) compared with 3.05 (95% CI, 0.79-5.30) for the final 5 years (P = .32). The demographic characteristics of the 19 patients are provided in Table 1. There was no predilection for sex, and the mean age at diagnosis was 2.1 years (range, birth to 17.6 years). Three patients (16%) were African American, a significantly higher proportion than that in the study population (2.7%; P < .001). The patients also included 1 set of identical twins. Six (32%) of the 19 patients were born prematurely and 8 (42%) were firstborn. One patient had intrauterine growth retardation and 3 (16%) were born to mothers with gestational diabetes mellitus.

Table Graphic Jump LocationTable 1.  Demographic Characteristics and Prenatal Risk Factors in 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008

The ocular characteristics of the 19 pediatric patients identified in this study are listed in Table 2. Sixteen patients (84%) had bilateral ONH and 3 (16%) had unilateral involvement of the right eye. At the initial visit, 9 patients (47%) had decreased visual acuity, 8 (42%) had strabismus, 5 (26%) had nystagmus, and 1 (5%) had amblyopia. Eleven patients had other ocular abnormalities (Table 2).

Table Graphic Jump LocationTable 2.  Ocular Characteristics at Initial Examination in 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008

The associated endocrine and neurologic abnormalities in the 19 study patients are listed in Table 3. Five patients (26%), all with bilateral ONH, had an endocrine abnormality, including 4 with pituitary gland abnormalities seen with neuroimaging. One patient had panhypopituitarism and 3 had varied pituitary dysfunction, including 2 each with growth hormone deficiency, thyroid hormone deficiency, and diabetes insipidus and 1 with adrenal insufficiency. The fifth patient had isolated central precocious puberty. In 3 patients, endocrine abnormalities developed within 6 weeks after birth, and the other 2 had identifiable endocrine dysfunction by about 7 years of age.

Table Graphic Jump LocationTable 3.  Endocrine, Neurologic, and Developmental Disorders in 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008

Twelve (63%) of the 19 patients were evaluated with neuroimaging. Ten (53%), all with bilateral ONH, had an underlying neurologic abnormality identified either clinically or with imaging. The most common neurologic abnormalities identified were cerebral palsy and microcephaly in 3 patients (16%) each. Two patients (11%) had agenesis of the septum pellucidum and 2 (11%) had corpus callosum abnormalities. Twelve patients (63%) also had a diagnosis of developmental delay; the most common deficits were profound mental retardation and motor and communication delays.

Optic nerve hypoplasia was also diagnosed in conjunction with assorted systemic disorders. One patient died shortly after birth, and trisomy 13 and bilateral ONH were diagnosed at autopsy. One patient had epidermal nevus syndrome, and another had Zellweger (cerebrohepatorenal) syndrome; both had bilateral ONH. A set of identical twins had bilateral ONH and oculocutaneous albinism.

The mean length of follow-up for the cohort was 2.2 years (range, 0-12.4 years). Table 4 describes the ophthalmologic, endocrine, and neurologic management of the 19 study patients. Nine patients required eyeglasses, 8 for visual acuity and 1 to correct strabismus. Two patients underwent strabismus surgery and 2 were treated for amblyopia. Of the 5 patients with endocrine abnormalities, growth hormone therapy was required in 2, steroid hormone in 3, thyroid hormone in 3, and a gonadotropin-releasing hormone agonist in 1. Three patients died within the follow-up period.

Table Graphic Jump LocationTable 4.  Management of 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008

We report the population-based incidence rate of ONH and the prevalence of associated endocrine and neurologic abnormalities in a cohort of pediatric patients living in Olmsted County, Minnesota. Optic nerve hypoplasia occurred in 1 in 2287 live births. Associated findings included significant ocular comorbidity in 65%, developmental delay in 63%, neurologic abnormalities in 53%, and confirmed pituitary dysfunction in 26%.

To our knowledge, this is the first study to determine the incidence of ONH in a North American population. In 1981, Acers3 estimated the incidence of ONH to be 2 cases per 100 000 residents based on his incomplete review of 45 patients in the “state community” of Oklahoma. A more recent study from Sweden estimated an incidence of 6.3 per 100 000,6 and the incidence in England was estimated to be higher still, at 10.9 per 100 000.7 Findings of several recent studies have suggested that the incidence of ONH has been rising, possibly owing to enhanced awareness of the condition.10 Because of the small number of cases in our study, we could not demonstrate any statistically significant changes in incidence over time. However, it is worth noting that the incidence rate during the last 5 years of the study was twice that of the first 5 years. Moreover, we could identify only 3 additional cases of ONH between 1965 and 1984, demonstrating that, although the difference was not statistically significant in this small study, more cases have been diagnosed in the most recent years.

Our incidence rate of ONH is significantly lower than other recent estimates, and the populations studied may explain this finding. The residents of Olmsted County during the years of our study were 95% white, were predominantly middle class, were more likely to have a college degree than the average American, and had a higher mean annual household income than the national average. The much higher estimate in England by Patel et al7 was observed in a predominantly urban area; they found an increased risk of ONH in 3 districts with high population densities and high rates of unemployment and teenage pregnancies. They suggested that the development of ONH is associated with environmental or lifestyle factors linked to deprivation in this population.7 The significance of the increased proportion of African Americans with ONH in our study relative to their percentage within Olmsted County is unknown, but the discrepancy may be due in part to small sample size.

Multiple studies have suggested an association of ONH with various gestational and environmental conditions, particularly primiparity, prematurity, young maternal age, gestational diabetes mellitus, and alcohol and tobacco abuse.2,1116 The most common conditions associated with ONH in our study were primiparity and prematurity. Thirteen percent of affected infants were born to mothers with a history of perinatal alcohol or tobacco abuse, consistent with prior estimates. Contrary to previous reports indicating an association of young maternal age with ONH,12,13,17 the mean maternal age at delivery in this cohort was 30 years. One set of twins with ONH was identified in this group, suggesting that a common genetic or gestational factor may play a role in the disorder.

Sixteen (84%) of the 19 incident cases of ONH in the present study were bilateral, consistent with previous estimates, ranging from 75% to 93%.3,5,16,18 The most common ocular findings at initial examination were decreased visual acuity (47%), strabismus (42%), and nystagmus (26%). In a 2-year-old child who had amblyopia at initial examination, ONH was not diagnosed until the child was 4 years old. In another child whose ONH was diagnosed at birth, amblyopia developed at a later age. This highlights the importance of not only early screening and diagnosis of ONH but also proper ophthalmologic management to curtail the development of treatable sequelae, such as amblyopia.

There has been significant discord regarding the prevalence of endocrine abnormalities among patients with ONH. Several retrospective studies have found endocrine dysfunction to vary from 6% to 81%.11,1822 In a prospective study including 46 children with ONH, Ahmad et al18 found that 71.7% developed endocrine dysfunction by 5 years of age. However, all prior studies were performed in large medical referral centers. In the present study, 5 patients (26%) had endocrine abnormalities by 7 years of age.

Ten (53%) of the study patients had neurologic abnormalities either at clinical examination or with neuroimaging. Three patients (16%) had cerebral palsy, an association that, to our knowledge, has been described only once previously.11 Twelve patients (63%) in this study had a diagnosis of developmental delay. There was a broad range of developmental phenotypes in these patients, from normal intellect to profound mental retardation, as is often the case among children with ONH.11 The most common deficits included profound mental retardation and motor and communication delays. These findings were consistent with previous estimates of neurodevelopmental deficits in children with ONH.5,11

Findings from several studies have suggested that children with bilateral involvement are more likely to develop endocrine and neurodevelopmental deficits,5,11,12,18,20,23 and our findings further reinforce that hypothesis. All 5 patients with endocrine deficits and all 10 with neurologic abnormalities had bilateral ONH, as did all but 1 patient with developmental abnormalities. Of the 3 patients with unilateral ONH, only 1 had an additional diagnosis (developmental delay).

One set of identical twins with oculocutaneous albinism and bilateral ONH were identified in our cohort, supporting the findings of others. Spedick and Beauchamp24 noted ONH in 6 eyes of 4 patients in a review of 12 patients with ocular or oculocutaneous albinism, and Charles et al25 found ONH in 29 of 148 eyes of patients with albinism. More recently, Schmitz et al26 reported a significant difference in optic nerve diameter by magnetic resonance imaging between patients with albinism and controls.

Our study had several limitations, including its retrospective design and imprecise follow-up. The study design may not have captured all patients and all episodes of disease because some patients with ONH or their parents may have sought care outside Olmsted County or avoided evaluation altogether. Moreover, because of the potential for misdiagnosis or miscoding or because some children with ONH may have never developed visual, endocrine, or neurologic deficits, the incidence of ONH may have been underestimated in this population. Although the mean duration of follow-up in this cohort should be sufficient to enable the detection of endocrine, neurologic, or developmental abnormalities, we may have underestimated the rates of these disorders among this cohort. This rate may be further underestimated because of the absence of neuroimaging in 7 of the 19 study patients.

Our study is also limited by the region where it was performed. Because the ethnic composition of Olmsted County was 95% white during the years of the study, we cannot extrapolate our findings to populations not represented by this cohort. Recognizing these weaknesses and assuming a population of 76 620 000 citizens younger than 19 years (2000 US Census), we estimate 1838 new cases of ONH each year in the United States. Although ONH is relatively uncommon, each child with this diagnosis should receive specialized neurologic and endocrine evaluations given the high rates of developmental delay (63%), neurologic deficits (53%), and endocrine dysfunction (26%) in this population.

In conclusion, our study found that ONH was diagnosed in 1 in 2287 children in Olmsted County during a 25-year period. Although limited by small sample size, our data suggest that the incidence of ONH has remained stable in this US population. A majority of patients with ONH have associated neurodevelopmental or endocrine deficits, necessitating early diagnosis and proper management in pediatric patients.

Corresponding Author: Brian G. Mohney, MD, Department of Ophthalmology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (mohney@mayo.edu).

Submitted for Publication: July 24, 2012; final revision received December 22, 2012; accepted January 5, 2013.

Published Online: May 2, 2013. doi:10.1001/jamaophthalmol.2013.65

Author Contributions:Study concept and design: Mohney, Young.

Acquisition of data: Young.

Analysis and interpretation of data: Young, Diehl.

Drafting of the manuscript: Young.

Critical revision of the manuscript for important intellectual content: Mohney, Diehl.

Statistical analysis: Young, Diehl.

Obtained funding: Mohney.

Administrative, technical, and material support: Mohney.

Study supervision: Mohney.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was made possible in part by the Rochester Epidemiology Project (grant R01-AG034676 from the National Institute on Aging) and by an unrestricted grant from Research to Prevent Blindness Inc.

Steinkuller  PG, Du  L, Gilbert  C, Foster  A, Collins  ML, Coats  DK.  Childhood blindness. J AAPOS. 1999;3(1):26-32.
PubMed   |  Link to Article
Borchert  M, Garcia-Filion  P.  The syndrome of optic nerve hypoplasia. Curr Neurol Neurosci Rep. 2008;8(5):395-403.
PubMed   |  Link to Article
Acers  TE.  Optic nerve hypoplasia: septo-optic-pituitary dysplasia syndrome. Trans Am Ophthalmol Soc. 1981;79:425-457.
PubMed
Birkebaek  NH, Patel  L, Wright  NB,  et al.  Optic nerve size evaluated by magnetic resonance imaging in children with optic nerve hypoplasia, multiple pituitary hormone deficiency, isolated growth hormone deficiency, and idiopathic short stature. J Pediatr. 2004;145(4):536-541.
PubMed   |  Link to Article
Garcia-Filion  P, Epport  K, Nelson  M,  et al.  Neuroradiographic, endocrinologic, and ophthalmic correlates of adverse developmental outcomes in children with optic nerve hypoplasia: a prospective study. Pediatrics. 2008;121:653-659.
PubMed   |  Link to Article
Blohmé  J, Tornqvist  K.  Visual impairment in Swedish children, III: diagnoses. Acta Ophthalmol Scand. 1997;75(6):681-687.
PubMed   |  Link to Article
Patel  L, McNally  RJ, Harrison  E, Lloyd  IC, Clayton  PE.  Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J Pediatr. 2006;148(1):85-88.
PubMed   |  Link to Article
Kurland  LT, Molgaard  CA.  The patient record in epidemiology. Sci Am. 1981;245(4):54-63.
PubMed   |  Link to Article
St Sauver  JL, Grossardt  BR, Leibson  CL, Yawn  BP, Melton  LJ  III, Rocca  WA.  Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project. Mayo Clin Proc. 2012;87(2):151-160.
PubMed   |  Link to Article
Blohmé  J, Bengtsson-Stigmar  E, Tornqvist  K.  Visually impaired Swedish children: longitudinal comparisons 1980-1999. Acta Ophthalmol Scand. 2000;78(4):416-420.
PubMed   |  Link to Article
Garcia  ML, Ty  EB, Taban  M, David Rothner  A, Rogers  D, Traboulsi  EI.  Systemic and ocular findings in 100 patients with optic nerve hypoplasia. J Child Neurol. 2006;21(11):949-956.
PubMed   |  Link to Article
Zeki  SM, Dutton  GN.  Optic nerve hypoplasia in children. Br J Ophthalmol. 1990;74(5):300-304.
PubMed   |  Link to Article
Tornqvist  K, Ericsson  A, Källén  B.  Optic nerve hypoplasia: risk factors and epidemiology. Acta Ophthalmol Scand. 2002;80(3):300-304.
PubMed   |  Link to Article
Ribeiro  IM, Vale  PJ, Tenedorio  PA, Rodrigues  PA, Bilhoto  MA, Pereira  HC.  Ocular manifestations in fetal alcohol syndrome. Eur J Ophthalmol. 2007;17(1):104-109.
PubMed
Stromland  K.  Ocular abnormalities in the fetal alcohol syndrome. Acta Ophthalmol Scand Suppl. 1985;171:1-50.
PubMed
Hellström  A, Wiklund  L-M, Svensson  E.  The clinical and morphologic spectrum of optic nerve hypoplasia. J AAPOS. 1999;3(4):212-220.
PubMed   |  Link to Article
Margalith  D, Jan  JE, McCormick  AQ, Tze  WJ, Lapointe  J.  Clinical spectrum of congenital optic nerve hypoplasia: review of 51 patients. Dev Med Child Neurol. 1984;26(3):311-322.
PubMed   |  Link to Article
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. J Pediatr. 2006;148(1):78-84.
PubMed   |  Link to Article
Birkebaek  NH, Patel  L, Wright  NB,  et al.  Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003;88(11):5281-5286.
PubMed   |  Link to Article
Traggiai  C, Stanhope  R.  Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr. 2002;140(2):252-255.
PubMed   |  Link to Article
Siatkowski  RM, Sanchez  JC, Andrade  R, Alvarez  A.  The clinical, neuroradiographic, and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology. 1997;104(3):493-496.
PubMed   |  Link to Article
Riedl  SW, Müllner-Eidenböck  A, Prayer  D, Bernert  G, Frisch  H.  Auxological, ophthalmological, neurological and MRI findings in 25 Austrian patients with septo-optic dysplasia (SOD): preliminary data. Horm Res. 2002;58(suppl 3):16-19.
PubMed   |  Link to Article
Skarf  B, Hoyt  CS.  Optic nerve hypoplasia in children: association with anomalies of the endocrine and CNS. Arch Ophthalmol. 1984;102(1):62-67.
PubMed   |  Link to Article
Spedick  MJ, Beauchamp  GR.  Retinal vascular and optic nerve abnormalities in albinism. J Pediatr Ophthalmol Strabismus. 1986;23(2):58-63.
PubMed
Charles  SJ, Green  JS, Grant  JW, Yates  JR, Moore  AT.  Clinical features of affected males with X linked ocular albinism. Br J Ophthalmol. 1993;77(4):222-227.
PubMed   |  Link to Article
Schmitz  B, Schaefer  T, Krick  CM, Reith  W, Backens  M, Käsmann-Kellner  B.  Configuration of the optic chiasm in humans with albinism as revealed by magnetic resonance imaging. Invest Ophthalmol Vis Sci. 2003;44(1):16-21.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Demographic Characteristics and Prenatal Risk Factors in 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008
Table Graphic Jump LocationTable 2.  Ocular Characteristics at Initial Examination in 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008
Table Graphic Jump LocationTable 3.  Endocrine, Neurologic, and Developmental Disorders in 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008
Table Graphic Jump LocationTable 4.  Management of 19 Pediatric Patients With Optic Nerve Hypoplasia in Olmsted County, Minnesota, 1984-2008

References

Steinkuller  PG, Du  L, Gilbert  C, Foster  A, Collins  ML, Coats  DK.  Childhood blindness. J AAPOS. 1999;3(1):26-32.
PubMed   |  Link to Article
Borchert  M, Garcia-Filion  P.  The syndrome of optic nerve hypoplasia. Curr Neurol Neurosci Rep. 2008;8(5):395-403.
PubMed   |  Link to Article
Acers  TE.  Optic nerve hypoplasia: septo-optic-pituitary dysplasia syndrome. Trans Am Ophthalmol Soc. 1981;79:425-457.
PubMed
Birkebaek  NH, Patel  L, Wright  NB,  et al.  Optic nerve size evaluated by magnetic resonance imaging in children with optic nerve hypoplasia, multiple pituitary hormone deficiency, isolated growth hormone deficiency, and idiopathic short stature. J Pediatr. 2004;145(4):536-541.
PubMed   |  Link to Article
Garcia-Filion  P, Epport  K, Nelson  M,  et al.  Neuroradiographic, endocrinologic, and ophthalmic correlates of adverse developmental outcomes in children with optic nerve hypoplasia: a prospective study. Pediatrics. 2008;121:653-659.
PubMed   |  Link to Article
Blohmé  J, Tornqvist  K.  Visual impairment in Swedish children, III: diagnoses. Acta Ophthalmol Scand. 1997;75(6):681-687.
PubMed   |  Link to Article
Patel  L, McNally  RJ, Harrison  E, Lloyd  IC, Clayton  PE.  Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J Pediatr. 2006;148(1):85-88.
PubMed   |  Link to Article
Kurland  LT, Molgaard  CA.  The patient record in epidemiology. Sci Am. 1981;245(4):54-63.
PubMed   |  Link to Article
St Sauver  JL, Grossardt  BR, Leibson  CL, Yawn  BP, Melton  LJ  III, Rocca  WA.  Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project. Mayo Clin Proc. 2012;87(2):151-160.
PubMed   |  Link to Article
Blohmé  J, Bengtsson-Stigmar  E, Tornqvist  K.  Visually impaired Swedish children: longitudinal comparisons 1980-1999. Acta Ophthalmol Scand. 2000;78(4):416-420.
PubMed   |  Link to Article
Garcia  ML, Ty  EB, Taban  M, David Rothner  A, Rogers  D, Traboulsi  EI.  Systemic and ocular findings in 100 patients with optic nerve hypoplasia. J Child Neurol. 2006;21(11):949-956.
PubMed   |  Link to Article
Zeki  SM, Dutton  GN.  Optic nerve hypoplasia in children. Br J Ophthalmol. 1990;74(5):300-304.
PubMed   |  Link to Article
Tornqvist  K, Ericsson  A, Källén  B.  Optic nerve hypoplasia: risk factors and epidemiology. Acta Ophthalmol Scand. 2002;80(3):300-304.
PubMed   |  Link to Article
Ribeiro  IM, Vale  PJ, Tenedorio  PA, Rodrigues  PA, Bilhoto  MA, Pereira  HC.  Ocular manifestations in fetal alcohol syndrome. Eur J Ophthalmol. 2007;17(1):104-109.
PubMed
Stromland  K.  Ocular abnormalities in the fetal alcohol syndrome. Acta Ophthalmol Scand Suppl. 1985;171:1-50.
PubMed
Hellström  A, Wiklund  L-M, Svensson  E.  The clinical and morphologic spectrum of optic nerve hypoplasia. J AAPOS. 1999;3(4):212-220.
PubMed   |  Link to Article
Margalith  D, Jan  JE, McCormick  AQ, Tze  WJ, Lapointe  J.  Clinical spectrum of congenital optic nerve hypoplasia: review of 51 patients. Dev Med Child Neurol. 1984;26(3):311-322.
PubMed   |  Link to Article
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. J Pediatr. 2006;148(1):78-84.
PubMed   |  Link to Article
Birkebaek  NH, Patel  L, Wright  NB,  et al.  Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003;88(11):5281-5286.
PubMed   |  Link to Article
Traggiai  C, Stanhope  R.  Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr. 2002;140(2):252-255.
PubMed   |  Link to Article
Siatkowski  RM, Sanchez  JC, Andrade  R, Alvarez  A.  The clinical, neuroradiographic, and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology. 1997;104(3):493-496.
PubMed   |  Link to Article
Riedl  SW, Müllner-Eidenböck  A, Prayer  D, Bernert  G, Frisch  H.  Auxological, ophthalmological, neurological and MRI findings in 25 Austrian patients with septo-optic dysplasia (SOD): preliminary data. Horm Res. 2002;58(suppl 3):16-19.
PubMed   |  Link to Article
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