eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Tuberous Sclerosis

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Sergiusz Jozwiak, MD, PhD, Head, Professor, Department of Child Neurology, The Children's Memorial Health Institute of Warsaw, Poland; Robert Pedersen, MD, Chief of Child Neurology, Assistant Professor, Departments of Pediatrics and Neurology, Tripler Army Medical Center
Contributor Information and Disclosures

Updated: Feb 17, 2009

Introduction

Background

Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease. Tuberous sclerosis complex is inherited in an autosomal dominant pattern, although the rate of spontaneous mutation is high. Formerly characterized by the clinical triad of mental retardation, epilepsy, and facial angiofibromas, patients with tuberous sclerosis complex may present with a broad range of clinical symptoms because of variable expressivity. Tuberous sclerosis complex may affect many organs, most commonly the brain, skin, eyes, heart, kidneys, and lungs. Common features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), facial angiofibromas, hypomelanotic spots known as Fitzpatrick patches (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas.

Recently, mutations in 2 genes (TSC1 and TSC2) have been determined to cause tuberous sclerosis complex; however, current diagnostic criteria continue to be based on clinical manifestations.1

Pathophysiology

Tuberous sclerosis complex has a broad clinical spectrum and affects almost every organ system. Many of the clinical symptoms are due to the development and growth of hamartomas. Cortical tubers in the brain are typically located at the gray-white matter interface, commonly in the frontal and parietal lobes. Cortical tubers are composed of abnormal glial and neural cells, and the size, number, and location vary among patients. The number of tubers may correlate with the severity of seizures. Other CNS manifestations include SENs and SEGAs. SENs are typically located on the surface of the lateral ventricles, giving a candle-dripping appearance, and they tend to calcify during childhood. SENs occasionally give rise to SEGAs, which develop in the Monro foramen and may cause signs and symptoms of hydrocephalus and increased intracranial pressure as they enlarge.

Skin lesions are extremely common in patients with tuberous sclerosis complex. Skin lesions include ash-leaf spots, confetti lesions, facial angiofibromas, shagreen patches, fibrous plaques, and periungual fibromas. The hypopigmentation of ash-leaf spots is due to smaller melanosomes and defective transfer of melanin to keratinocytes. Fibromas, plaques, and patches are due to fibrosis with abnormal collagen and blood vessel accumulation.

Renal manifestations of tuberous sclerosis complex include angiomyolipomas and renal cysts. Angiomyolipomas, found in 70-80% of patients with tuberous sclerosis complex, are composed of blood vessels, smooth muscle, adipose tissue, and connective tissue. The gene for polycystic kidney disease (PKD), PKD1, is contiguous with the TSC2 gene on chromosome 16, and patients with tuberous sclerosis complex occasionally have symptoms of PKD.

Cardiac rhabdomyomas often present at birth or during infancy but may be detected as early as 20 weeks' gestation using fetal ultrasonography. These hamartomas, which are usually multiple and intramural, may cause abnormal valve function, outflow obstruction, decreased contractility, cardiomyopathy, and arrhythmias. Usually, cardiac rhabdomyomas are asymptomatic and spontaneously resolve as the child ages if the rhabdomyoma does not cause outflow obstruction during the neonatal period.

Lymphangioleiomyomatosis (LAM) and pulmonary cysts are 2 pulmonary lesions that may develop. These lesions develop almost exclusively in women in the third or fourth decade of life, although fewer than 1% of females with tuberous sclerosis complex exhibit these lesions. The lesions are composed of blood vessels, adipose tissue, and smooth muscle in abnormal arrangements. Spontaneous pneumothorax may occur, and pulmonary fibrosis and hypertension may lead to cor pulmonale.

Ocular involvement includes retinal hamartomas or astrocytomas that may calcify but rarely lead to decreased visual acuity or other symptoms. Phalangeal cysts may develop in the hands and feet, and sclerotic lesions may develop in the pelvis or the spine. Asymptomatic pitting of dental enamel is common in the permanent teeth of patients with tuberous sclerosis complex.

The genes responsible for tuberous sclerosis complex have been identified. Tuberous sclerosis complex is caused by a mutation in either TSC1 or TSC2, which are tumor suppressor genes that work together to facilitate tumor suppression.2 TSC1, located on chromosome 9, encodes for the protein hamartin; TSC2, located on chromosome 16, encodes for the protein tuberin. The function and interaction of these proteins are not yet fully understood, although they may function as tumor suppressors. Knudson's 2-hit model of tumorigenesis mandates that a second-hit mutation and resulting loss of heterozygosity (LOH) of a tumor suppressor gene is necessary for tumor formation. LOH is commonly found in several types of hamartomas formed in the process of tuberous sclerosis, but not in brain lesions that contain characteristic giant cells.3

Hamartin and tuberin are believed to have a role in growth and differentiation of cells. Both proteins are found throughout the body and interact with each other. Little attention is given to the recently discovered role of the TSC1/TSC2 complex in gene transcription via the Wnt signaling pathway. Recently, hamartin and tuberin have been found to modulate gene transcription via beta-catenin.4

Evidence also suggests that extracellular signal-regulated kinase (ERK) is specifically implicated in the pathogenesis of hamartomas.5 Jozwiak et al postulate that ERK activation consistently detected in different tuberous sclerosis–associated tumors is a molecular trigger for the development of these neoplasms.6 Cardiac rhabdomyoma arising in tuberous sclerosis may progress due to Erk potentiation.7

Frequency

United States

Tuberous sclerosis complex affects approximately 40,000 people in the United States. The incidence is estimated to be 1 case per 6000 live births, with a prevalence of 1 in 10,000 births. The prevalence of tuberous sclerosis complex was previously estimated to be 1 in 50,000-100,000 births. Revision of the diagnostic criteria and improved recognition of the disease complex by physicians have resulted in an increased prevalence rate. Further evaluation of family members may also result in recognition of tuberous sclerosis complex in people with less severe phenotypes, which also increases the prevalence rate. Unaffected parents of children with tuberous sclerosis complex have a recurrence risk of 1-2% in subsequent pregnancies. Affected parents have a 50% chance of transmission to offspring because of the autosomal dominant inheritance pattern. Incidence of gonadal mosaicism is approximately 10-25%. Approximately 0.1-0.7% of patients with mental retardation have tuberous sclerosis complex.

International

Estimates indicate that 2,000,000 people have tuberous sclerosis complex worldwide.

Mortality/Morbidity

Overall, the most common cause of death in patients with tuberous sclerosis complex is status epilepticus or bronchopneumonia. The next most frequent cause of death in patients with tuberous sclerosis complex is renal failure. Morbidity is associated in the following organ systems:

  • CNS manifestations: Seizures, hydrocephalus, mental retardation, and autism or pervasive developmental disorder (PDD) are commonly associated with morbidity in children with tuberous sclerosis complex.
    • Seizures are the most common cause of morbidity and affect more than one half of patients with tuberous sclerosis complex. Infantile spasms affect approximately one third of patients and are often one of the early symptoms of tuberous sclerosis complex. The risks of refractory seizures and decreased cognitive function, with earlier age of seizure onset, are higher. Earlier and more aggressive treatment may improve outcome.
    • The growth of SEGAs may lead to hydrocephalus, although growth is gradual and patients often do not become symptomatic until significant hydrocephalus has developed. Patients may then experience neurologic sequelae, including blindness. Patients often require neurosurgery and shunt placement.
    • Approximately 50-85% of children with tuberous sclerosis complex have mental retardation. Nearly all patients with mental retardation have seizures, although the reverse is not always true. Seizures and mental retardation may be concomitant.
    • Autism or PDD is present in 15-85% of children with tuberous sclerosis complex. The typical pattern of male bias in autism does not extend to patients with tuberous sclerosis complex.
    • Various behavioral disorders, including sleep disorders, hyperactivity, aggression, and schizophrenia, may be present in some individuals. Patients with tuberous sclerosis complex who have normal intelligence may be prone to developmental language disorders.
  • Dermatologic manifestations: Various skin lesions are present in as many as 95% of patients with tuberous sclerosis complex. Facial angiofibromas, present in 75% of patients, cause the most morbidity because of the disfiguring cosmetic effects. Previously treated with dermal abrasion techniques, they are currently treated more successfully using laser therapy.
  • Renal manifestations: Approximately 70-80% of patients with tuberous sclerosis complex have either renal cysts, which are more common in children, or angiomyolipomas, which are more common in adults. Renal failure or hypovolemic shock due to bleeding angiomyolipomas may lead to death. Renal failure is the second most common cause of death in patients with tuberous sclerosis complex, following status epilepticus or bronchopneumonia in some patients with mental retardation. The risk of bleeding increases when angiomyolipomas are larger than 4 cm. Rarely, renal lesions undergo differentiation to renal cell carcinoma.
  • Cardiac manifestations: Rhabdomyomas often develop at 22-26 weeks’ gestation. They may cause fetal death due to nonimmune hydrops fetalis. These benign tumors may cause valvular dysfunction, outflow obstruction in 1-2 ventricles, decreased contractility, and cardiomyopathy. Rhabdomyomas may also predispose patients to cardiac arrhythmias. In most patients, if outflow obstruction does not occur during the neonatal period, the lesions frequently resolve spontaneously or shrink after several years. Although cardiac rhabdomyomas are common, they do not usually cause mortality.
  • Pulmonary manifestations: LAM predominantly occurs in females with tuberous sclerosis complex, although fewer than 1% of females are affected. However, LAM is the most common cause of death in patients with tuberous sclerosis complex, when present. Pulmonary hypertension and fibrosis may lead to cor pulmonale. Pneumothorax or pulmonary failure is often the final cause of death in patients with LAM or pulmonary cysts.

Race

Tuberous sclerosis complex occurs with equal frequency in all races.

Sex

No sex predilection is noted in this autosomal dominant disease. Tuberous sclerosis complex in females tends to be associated with higher morbidity and mortality rates because the incidence of lung involvement is higher in females than in males.

Age

Tuberous sclerosis complex is a congenital disorder, although age at diagnosis may range from birth to adulthood. Patients who are not severely affected may be diagnosed only when a family member is discovered to have tuberous sclerosis complex and all family members are evaluated. Younger patients typically present with cardiac rhabdomyomas, brain tumors, ash-leaf spots, or seizures, particularly infantile spasms. Diagnosis at a later age is often due to CNS and dermatologic manifestations.

Clinical

History

Children with tuberous sclerosis complex (TSC) may have a broad range of symptoms and signs, ranging from subclinical findings to severe handicaps, because of variable expression.

A family history of tuberous sclerosis complex may not be discovered if tuberous sclerosis complex is caused by a spontaneous mutation or if a family member has subclinical disease. Obtain a history and detailed physical evaluation of family members. This includes a history of tuberous sclerosis complex, seizures, mental retardation, skin manifestations, or other findings consistent with tuberous sclerosis complex.

Clinical symptoms of tuberous sclerosis complex in 4 patients with an identical TSC2 mutation were assessed.8 Epilepsy, depigmented spots, and periventricular calcification and cortical tubers were evident in all 4 patients; cardiac rhabdomyoma and angiomyolipoma of the kidneys were evident in 3 patients; and mental retardation and forehead fibroma were evident in 2 patients. Thus, tuberous sclerosis complex symptoms varied in patients with the identical type of TSC2 mutation. The main symptoms were present in all or most patients; the clinical picture also differed based on age.

Usefulness of tuberous sclerosis complex diagnostic criteria in pediatric patients

The Tuberous Sclerosis Complex 1998 Consensus Conference clinical criteria represented an important advance in the diagnosis of tuberous sclerosis complex.9 However, many findings regarded as highly specific for tuberous sclerosis complex are not apparent until late childhood or adulthood.10 Physicians should be aware of the criteria frequency in different stages of tuberous sclerosis complex in children.

  • CNS symptoms: The most common and severe CNS manifestations of tuberous sclerosis complex include seizures, including infantile spasms, and mental retardation. Other symptoms include autism or pervasive developmental disorder (PDD), aggressive behavior, schizophrenia, and sleep disturbances. Sleep disturbances may be displayed by decreased overall sleep time and frequent nocturnal awakenings.
  • Dermatologic symptoms: Hypopigmented spots known as Fitzpatrick patches (ash-leaf spots) are typically the first dermatologic manifestations of tuberous sclerosis complex.11 Other possible lesions include confetti lesions, facial angiofibromas, shagreen patches, periungual or ungual fibromas, and caf é au lait spots.
  • Renal symptoms: Flank pain is the most common renal symptom. Other symptoms include hematuria, hypertension, and, rarely, hemorrhagic shock or renal failure, which may develop in severe cases. Renal symptoms are rare during childhood and are not present in all patients with renal disease.
  • Cardiac symptoms
    • Cardiac rhabdomyomas may cause heart failure or arrhythmia, even in the presence of normal echocardiogram findings. Patients with rhabdomyomas are usually asymptomatic. Rhabdomyomas often regress with time, although the patient remains at risk for arrhythmia.
    • A case report of molecular confirmation identified multiple cardiac rhabdomyomas as a sole symptom of tuberous sclerosis complex.
    • A child was described with multiple cardiac rhabdomyomas that were identified using routine fetal ultrasonography.12 Molecular genetic studies identified a TSC2 gene missense mutation. At age 6 years, he had no skin manifestations of tuberous sclerosis complex, although CT scan of the brain revealed 2 periventricular calcifications consistent with the molecular diagnosis. Molecularly confirmed tuberous sclerosis complex in a child with multiple cardiac rhabdomyomas and no other clinical manifestations of the disease had not been previously described. All infants with multiple cardiac rhabdomyomas were proposed to be given a tentative diagnosis of tuberous sclerosis complex.
  • Pulmonary symptoms: These predominantly affect females, although fewer than 1% of females with tuberous sclerosis complex have pulmonary pathology. When present, symptoms include dyspnea, hemoptysis, and development of spontaneous pneumothorax.
  • Oral symptoms: Most oral fibromas in tuberous sclerosis complex are gingival.13 Nearly all patients have dental pits.

Physical

In 1998, the National Institutes of Health Consensus Conference on Tuberous Sclerosis Complex developed revised diagnostic criteria, as follows:14

  • Definitive diagnosis - The presence of 2 major features or 1 major feature plus 2 minor features
  • Probable diagnosis - The presence of 1 major feature plus 1 minor feature
  • Possible diagnosis - The presence of 1 major feature or 2 minor features
Major and minor diagnostic features of tuberous sclerosis complex include the following:

  • Major features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), 3 or more ash-leaf spots, facial angiofibromas or forehead plaques, shagreen patches, ungual or periungual fibromas in the absence of trauma, cardiac rhabdomyomas, lymphangioleiomyomatosis (LAM), renal angiomyolipomas, or retinal hamartomas.
  • Minor features include dental pits, gingival fibromas, confetti skin lesions, bone cysts, hamartomatous rectal polyps, multiple renal cysts, other nonrenal hamartomas, achromic lesions of the retina, and radial migration lines of cerebral white matter.
Signs of tuberous sclerosis complex are as follows:

  • CNS manifestations
    • Seizures may develop during infancy or later. Infantile spasms or a hypsarrhythmia pattern on EEG findings may be present in infants with tuberous sclerosis complex. Other common seizure types in patients with tuberous sclerosis complex are complex partial and tonic-clonic seizures.
    • All patients with tuberous sclerosis complex who have mental retardation have seizures, but not all patients with seizures have mental retardation. Intelligence may be normal, or children may have mild, moderate, or severe mental retardation.
  • Dermatologic manifestations
    • Ash-leaf spots or hypopigmented lesions are typically the first dermatologic manifestation of tuberous sclerosis complex. The lesion is best observed using a Wood lamp. A Fitzpatrick patch or ash-leaf spot may be observed in the general population, but the presence of at least 3 lesions constitutes one of the major diagnostic criteria. These macules often come in other shapes, although most are polygonal, usually 0.5-2 cm in diameter, and resemble a thumbprint. In honor of their deceased describer, Thomas Fitzpatrick, they are termed Fitzpatrick patches.11
    • Hypomelanotic macules are overwhelmingly the most common early finding in tuberous sclerosis complex.15 Infants with seizures or other stigmata of tuberous sclerosis complex should be evaluated for these hypomelanotic macules and for other associated findings. Confetti lesions are also hypomelanotic lesions that cluster and have a reticulated or network appearance. They may develop anywhere on the skin.
    • Facial angiofibromas and forehead plaques usually present in patients older than 2 years. Facial angiofibromas are erythematous lesions located on the cheeks, nose, and chin, often sparing the upper lip. Growth is often increased during puberty, and angiofibromas are sometimes confused with acne. The presence of one or both of these lesions constitutes one of the major diagnostic criteria. The relationship between the presence of a forehead plaque and CNS involvement may be statistically significant in patients with tuberous sclerosis complex.16 If true, forehead plaque may be considered as a novel cutaneous marker of CNS involvement in tuberous sclerosis complex at an early stage.
    • A shagreen patch is a connective tissue hamartoma located in the lower back region. A shagreen patch has an orange peel or leathery texture and often presents in children aged 2-6 years but may not appear until puberty.
    • Ungual or periungual fibromas may appear in adolescents or adults with tuberous sclerosis complex. Fibromas may cause distortion of the nail or nailbed.
    • Café au lait spots occasionally develop in patients with tuberous sclerosis complex, although they are usually less common in patients with tuberous sclerosis complex than in those with neurofibromatosis.
  • Renal manifestations: Renal angiomyolipomas are considered one of the major diagnostic features of tuberous sclerosis complex. Angiomyolipomas are mesenchymal neoplasms that occur sporadically or are associated with tuberous sclerosis complex; they are generally considered to be benign. Malignant angiomyolipomas are rare; most are found to be epithelioid upon histopathological examination. A renal angiomyolipoma with a malignant epithelioid component was recently described in a patient with tuberous sclerosis complex.17 Renal cysts are also common, and 40-80% of patients with tuberous sclerosis complex have either renal angiomyolipomas or renal cysts. The presence of hypovolemic shock may result from bleeding angiomyolipomas. Renal failure may also be evident.
  • Cardiac manifestations: Arrhythmias due to cardiac rhabdomyomas may be noted. Signs of cardiac failure are rare but possible.
  • Pulmonary manifestations: Evidence of pneumothorax (including absence of breath sounds) due to progression of LAM may be observed.
  • Miscellaneous manifestations
    • A retinal hamartoma or astrocytoma may cause an abnormal red reflex that is sometimes confused with retinoblastoma. Visual acuity is typically not affected.
    • Dental pits in permanent teeth usually occur randomly on multiple teeth. They are more easily detected when teeth are stained.
    • Gingival fibromas can be noted upon visual inspection of the oral cavity.
    • A rectal hamartoma or polyp is occasionally detected using a digital rectal examination.
    • A low-grade hypothalamic papillary tumor recently described may extend the spectrum of neoplasms with tuberous sclerosis complex.18

Causes

Tuberous sclerosis complex is inherited in an autosomal dominant pattern. A parent with tuberous sclerosis complex has a 50% chance of transmitting the disease to offspring. Sporadic mutations are estimated to occur in approximately two thirds of cases.

  • Mutations in two genes, TSC1 and TSC2, have been identified as causes of tuberous sclerosis complex. TSC1 is located on chromosome 9 and was identified in 1997. This gene encodes for the protein hamartin. The protein tuberin is encoded by the gene TSC2. In 1993, TSC2, located on chromosome 16, was the first gene discovered to be involved in tuberous sclerosis complex. Approximately 50% of familial cases are due to TSC1, and the remaining 50% are due to TSC2. A mutation in the TSC2 gene is responsible for 75% of sporadic cases.
  • Currently, tuberous sclerosis complex is a clinical diagnosis because genetic testing is still expensive and rarely performed. Family members may also be tested on a clinical basis if a mutation is detected. Information regarding gene testing is available online from GeneTests.
  • Criteria for germline mosaicism have recently been outlined. Parents without evidence of either major or minor criteria of tuberous sclerosis complex who have 2 or more children with tuberous sclerosis complex meet the criteria for germline mosaicism. For this reason, parents who have no manifestations of tuberous sclerosis complex but who have one child with tuberous sclerosis complex should receive counseling regarding the 1-2% chance of having another child with tuberous sclerosis complex. The incidence of germline mosaicism is estimated to be approximately 10-25%.

More on Tuberous Sclerosis

Overview: Tuberous Sclerosis
Differential Diagnoses & Workup: Tuberous Sclerosis
Treatment & Medication: Tuberous Sclerosis
Follow-up: Tuberous Sclerosis
Multimedia: Tuberous Sclerosis
References
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Further Reading

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Keywords

tuberous sclerosis, tuberous sclerosis complex, TSC, Bourneville disease, neurocutaneous disease, mental retardation, epilepsy, facial angiofibromas, cortical tubers, subependymal nodules, SEN, subependymal giant cell astrocytomas, SEGA, hypomelanotic lesions, Fitzpatrick patches, ash-leaf spots, cardiac rhabdomyomas, renal angiomyolipomas, hamartomas, confetti lesions, shagreen patches, fibrous plaques, periungual fibromas, renal cysts, angiomyolipomas, spontaneous pneumothorax, cor pulmonale, phalangeal cysts, status epilepticus, bronchopneumonia

autism, pervasive developmental disorder, PDD, outflow obstruction, cardiomyopathy, arrhythmia, polycystic kidney disease, PKD, lymphangioleiomyomatosis, LAM, pulmonary cysts, phalangeal cysts, sclerotic lesions, hydrocephalus, sleep disorder, hyperactivity, schizophrenia, cafe au lait spots

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Sergiusz Jozwiak, MD, PhD, Head, Professor, Department of Child Neurology, The Children's Memorial Health Institute of Warsaw, Poland
Sergiusz Jozwiak, MD, PhD is a member of the following medical societies: Sigma Xi
Disclosure: Nothing to disclose.

Robert Pedersen, MD, Chief of Child Neurology, Assistant Professor, Departments of Pediatrics and Neurology, Tripler Army Medical Center
Robert Pedersen, MD is a member of the following medical societies: American Academy of Pediatrics and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Erawati V Bawle, MD, FAAP, FACMG, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine
Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Leonard G Feld, MD, PhD, MMM, FAAP, Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center
Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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