Description of Procedure or Service

Definitions

“Rett syndrome (RTS) is a severe neurodevelopmental disorder, defined by a regression of purposeful hand use and spoken language, usually caused by mutations in the MECP2 (methylCpG-binding protein 2) gene, affecting mostly females” (Neul, 2010).

Andrew Davis (Oct 25, 2010) DEFINES Rett syndrome (RTT) as “a rare genetic postnatal neurological disorder of the grey matter of the brain that almost exclusively affects females but has also been found in male patients”.

“Rett syndrome is a neurodevelopmental disorder that affects girls almost exclusively. It is characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability” (NINDS-NIH, 2016)

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for genetic testing for Rett syndrome when it is determined to be medically necessary because the medical criteria and guidelines shown below are met. 

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Testing for Rett Syndrome is covered

Genetic testing for MECP2, CDKL5 and/or FOXG1 mutation on the X chromosome of a child with developmental delay/intellectual disability and signs/symptoms of Rett syndrome is considered medically necessary to confirm a diagnosis when there is uncertainty in the clinical diagnosis.

When Genetic Testing for Rett Syndrome is not covered

All other indications for mutations testing for Rett syndrome, including prenatal screening and testing of family member are considered investigational.

Policy Guidelines

Background

Rett syndrome is a rare genetic, but severe brain disorder that affects girls. It's usually discovered in the first two years of life. It's rare -- only about one in 10,000 to 15,000 girls will develop the condition (Web MD web site, accessed Nov 15, 2016). Rett syndrome occurs in approximately 1:10,000 live female births in all geographies, and across all ethnicities. Although there's no cure, early identification and treatment may help girls and families who are affected by it.

The signs of this disorder are most easily confused with those of Angelman syndrome, cerebral palsy and autism. Rett syndrome was formerly classified as a pervasive developmental disorder by the Diagnostic and Statistical Manual of Mental Disorders (DSM), together with the autism spectrum disorders and childhood disintegrative disorder. Some argued against this classification because RTT is similar to non-autistic spectrum disorders such as fragile X syndrome, tuberous sclerosis, or Down syndrome where one can see autistic features. It was removed from the DSM5 in 2013 because it has a known molecular etiology.

The clinical picture associated with RTS is characterized by apparent normal development for the first 6 to 18 months of life, followed by the loss of intellectual functioning, loss of acquired fine and gross motor skills and communication. Purposeful use of the hands is replaced by repetitive stereotypical hand movements (Lotan, 2006). Other clinical observations include deceleration of head growth, seizures, disturbed breathing patterns, scoliosis, growth retardation and gait apraxia. RTS primarily affects girls, and is a prominent genetic cause of intellectual disability with an incidence of 1:10,000 female births (Lotan, 2006).

The severity and rate of progression of this disease can vary greatly, and there are a number of recognized atypical variants. The milder forms present with less severe regression and milder expression of the clinical characteristics of RTS. In the most severe forms there is no normal development period (Neul, 2010).

Signs and Symptoms:

Initial development is normal. Onset occurs between 6 and 18 months of age. During this time there are subtle developmental deviations and early indicators of Rett syndrome. A period of developmental stagnation is followed by developmental regression where language and motor milestones regress, purposeful hand use is lost, and acquired deceleration in the rate of head growth (resulting in microcephaly in some) is seen. Hand stereotypes are typical, and breathing irregularities such as hyperventilation, breath-holding, or sighing are seen in many. Early on, autistic-like behavior may be seen.

The infant with Rett syndrome often avoids detection until 6–18 months, owing to a relatively normal appearance and some developmental progress. However, closer scrutiny reveals disturbance of the normal spontaneous limb and body movements that are thought to be regulated in the brainstem. The brief period of developmental progress is followed by stagnation and regression of previously acquired skills. During regression, some features are similar to those of autism. It is, hence, easy to mistakenly diagnose Rett syndrome for autism.

Signs of Rett syndrome that are similar to autism:

• incontinence
• screaming fits
• inconsolable crying
• breath holding, hyperventilation & air swallowing
• avoidance of eye contact
• lack of social/emotional reciprocity
• markedly impaired use of nonverbal behaviors to regulate social interaction
• loss of speech
• sensory problems

Signs of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made):

• possible short stature, sometimes with unusual body proportions because of difficulty walking or malnutrition caused by difficulty swallowing
• hypotonia
• delayed or absent ability to walk
• gait/movement difficulties
• ataxia
• microcephaly in some - abnormally small head, poor head growth
• gastrointestinal problems
• some forms of spasticity
• chorea - spasmodic movements of hand or facial muscles
• dystonia
• bruxism – grinding of teeth

Signs may stabilize for many decades, particularly for interaction and cognitive function such as making choices. Asocial behavior may change to highly social behavior. Motor functions may slow as rigidity and dystonia appear. Seizures may be problematic, with a wide range of severity. Scoliosis occurs in most, and may require corrective surgery. Those who remain ambulatory tend to have less progression of scoliosis

Stages of the disorder?

Scientists generally describe four stages of Rett syndrome.

1. Stage I, called early onset, typically begins between 6 and 18 months of age. This stage is often overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first. The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can continue for more than a year.
2. Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months. Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language. Characteristic hand movements such as wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth often begin during this stage. The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements continue while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep. Some girls also display autistic-like symptoms such as loss of social interaction and communication. Walking may be unsteady and initiating motor movements can be difficult. Slowed head growth is usually noticed during this stage.
3. Stage III, or the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autistic-like features. A girl in stage III may show more interest in her surroundings and her alertness, attention span, and communication skills may improve. Many girls remain in this stage for most of their lives.
4. Stage IV, or the late motor deterioration stage, can last for years or decades. Prominent features include reduced mobility, curvature of the spine (scoliosis) and muscle weakness, rigidity, spasticity, and increased muscle tone with abnormal posturing of an arm, leg, or top part of the body. Girls who were previously able to walk may stop walking. Cognition, communication, or hand skills generally do not decline in stage IV. Repetitive hand movements may decrease and eye gaze usually improves

Cause and Genetics of RTS

Genetically, Rett syndrome (RTT) is caused by mutations in the gene MECP2 located on the X chromosome (which is involved in transcriptional silencing and epigenetic regulation of methylated DNA), and can arise sporadically or from germline mutations. In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. Rett syndrome is initially diagnosed by clinical observation, but the diagnosis is definitive when there is a genetic defect in the MECP2 gene. In some very rare cases, no known mutated gene can be found; possibly due to changes in MECP2 that are not identified by presently used techniques or mutations in other genes that may result in clinical similarities. It has been argued that Rett syndrome is in fact a neurodevelopmental condition as opposed to a neurodegenerative condition. One piece of evidence for this is that mice with induced Rett Syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MECP2 gene back when they are adults. This information has also helped lead to further studies aiming to treat the disorder.

Sporadic mutations

In at least 95% of Rett syndrome cases, the cause is a de novo mutation in the child. That is, it is not inherited from either parent. Parents are generally genotypically normal, without a MECP2 mutation.

In cases of the sporadic form of RTT, the mutated MECP2 is thought to be derived almost exclusively from a de novo mutation on the male copy of the X chromosome. It is not yet known what causes the sperm to mutate, and such mutations are rare.

Germline mutations

It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MECP2. In these cases, inheritance follows an Xlinked dominant pattern and is seen almost exclusively in females, as most males die in utero or shortly after birth. MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of RTT, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Rett syndrome affects one in every 12,500 female live births by age 12 years.

Genetics of RTS

RTS is inherited as an X-linked dominant disorder, with more than 99% of cases resulting from a de novo pathogenic variant (Christodoulou, 2012). Over 80 percent of patients with classical RTS have pathogenic mutations in the MECP2 gene, which is thought to control expression of several genes, including some involved in brain development. More than 200 mutations in MECP2 have been associated with RTS (Suter, 2014). Loss of hand skills was the most significant clinical predictor of a positive genetic test for mutations of MECP in girls (Knight, 2016). These mutations were considered to be lethal in males, however, disease‐causing MECP2 mutations have been identified in between 1.3% and 1.7% of mentally retarded male patients, with a wide range in severity from mild mental retardation to severe neonatal encephalopathy (Villard, 2007).

The pattern of X-chromosome inactivation influences the severity of the clinical disease (Archer, 2007) (Weaving, 2003). Rarely, a MECP2 variant may be inherited from a carrier mother in whom favorable skewing of X-chromosome inactivation results in minimal to no clinical findings. When the mother is a known carrier, the risk to her offspring of inheriting the MECP2 variant is 50% (Christodoulou, 2012)

Mutation in MECP2 does not necessarily equate to a clinical diagnosis of RTS. MECP2 mutations also have been reported in other clinical phenotypes, including individuals with an Angelman-like picture, nonsyndromic X-linked intellectual disability, autism, and presents in males as PPM-X syndrome (an X-linked genetic disorder characterized by psychotic disorders, parkinsonism and intellectual disability), and most commonly as neonatal encephalopathy (Williamson, 2002) (Suter, 2014; Livanage, 2014). MECP2 duplication presents in males as phenotype consisting of infantile hypotonia, recurrent respiratory infections and severe mental retardation.

Some patients with a clinical diagnosis of RTS, specifically with atypical variants do not appear to have mutations in the MECP2 gene, rather have mutations in one of two other genes, CDKL5 and FOXG1.

Mutation in MECP2 does not necessarily equate to a clinical diagnosis of RTS. MECP2 mutations also have been reported in other clinical phenotypes, including individuals with an Angelman-like picture, nonsyndromic X-linked intellectual disability, autism, and presents in males as PPM-X syndrome (an X-linked genetic disorder characterized by psychotic disorders, parkinsonism and intellectual disability), and most commonly as neonatal encephalopathy (Williamson, 2002) (Suter, 2014; Livanage, 2014). MECP2 duplication presents in males as phenotype consisting of infantile hypotonia, recurrent respiratory infections and severe mental retardation.

Some patients with a clinical diagnosis of RTS, specifically with atypical variants do not appear to have mutations in the MECP2 gene, rather have mutations in one of two other genes, CDKL5 and FOXG1.

Variants

The signs of Rett syndrome typical form are perfectly identified. In addition to the classical form of Rett syndrome, several «atypical forms» have been described over the year (Jeffrey et al, 2010). The main groups are:

Congenital variant (Rolando variant):

In this severe subtype of Rett syndrome, the development of the patients and their head circumference are abnormal from birth. The typical gaze of Rett syndrome patients is usually absent;

Zappella variant of Rett Syndrome or preserved speech variant:

In this subtype of Rett syndrome the patients acquire some manual skills and language is partially recovered around the age of 5 years (that is after the regression phase). Height, weight and head circumference are often in the normal range, and a good gross motor function can be observed. The Zappella variant is a milder form of Rett syndrome;

Hanefeld variant or early epilepsy variant:

In this form of Rett syndrome, the patients suffer from epilepsy before 5 months of age. The definition itself of the Rett syndrome has been refined over the years: as the atypical forms subsist near to the classical form, the "Rett Complex" terminology has been introduced.

Diagnosis

Physicians clinically diagnose Rett syndrome by observing signs and symptoms during the child's early growth and development, and conducting ongoing evaluations of the child's physical and neurological status.

Scientists have developed a genetic test to complement the clinical diagnosis, which involves searching for the MECP2 mutation on the child's X chromosome. Genetic testing can help confirm the diagnosis in 80% of girls with suspected Rett syndrome. It's possible that genetic testing can help predict severity.

Applicable Federal Regulations

No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.

Guidelines and Recommendations

Practice Guidelines and Position Statements

American Academy of Neurology/Child Neurology Society

In 2011, a quality standards subcommittee of American Academy of Neurology (AAN) and the Practice Committee of the Child Neurology Society issued an evidence report on the genetic and metabolic testing of children with global developmental delay. AAN recommended considering MECP2 mutation testing for all girls with unexplained moderate to severe developmental delay. Males with a history strongly suggestive of X-linked inheritance may be considered for testing of one or more individual XLID genes or for screening of the entire X chromosome (Michaelson, 2011).

American Academy of Pediatrics

A 2014 policy statement from the American Academy of Pediatrics (AAP) recommends MECP2 mutation analysis for girls with microcephaly or deceleration of head growth and other features of Rett syndrome, or who present with stereotypical hand-wringing movements and developmental regression. MECP2 gene mutations are extremely rare in males but may be considered in boys who present with clinical features of Rett syndrome or severe developmental regression. (Moeschler, 2014)

RettSearch

Neither AAN nor AAP have provided recommendations on when to use CDKL5 or FOXG1 testing. In 2010, RettSearch, a consortium of international clinical RTS specialists, suggested that patients who are negative for MECP2 mutations and who have a strong clinical diagnosis of RTS should be considered for further screening for the CDKL5 gene if there are early onset seizures or for the FOXG1 gene if there are congenital features (e.g., severe postnatal microcephaly).

American College of Medical Genetics

In 2013, the American College of Medical Genetics revised its evidence-based guideline for clinical genetics evaluation of autism spectrum disorders. Testing for MECP2 mutations is recommended as part of the diagnostic workup of females who present with an autistic phenotype. Routine MECP2 testing in males with autistic spectrum disorders is not recommended. However, when features of MECP2 duplications (e.g., drooling, recurrent respiratory infections, hypotonic facies) are present consider MECP2 duplication testing in boys with autism and such features. (Schaefer, 2013)

Rett Syndrome: Revised Diagnostic Criteria and Nomenclature

Neul and colleagues have revised diagnostic criteria and nomenclature for the diagnosis of Rett syndrome (Neul et al, 2010). This group provided clarifications for diagnosis of classic or typical RTT and atypical RTT and provided guidelines for molecular evaluation of specific variant forms of RTT. The authors were firm on their position that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. And, that their guidelines were developed for use in any future clinical practice and research. Neul and colleagues have proposed three distinct criteria for diagnosis of variant forms of RTT: preserved speech variant (Zapella variant), early seizure variant (Hanefeld variant) and congenital variant (Rolando variant). In addition to clinical findings, authors recommended identifying molecular genetics of each variant. In Zapella variant, mutations in MECP2 are found in majority cases, therefore the molecular analysis for MECP2 was recommended. On the contrary, In Hanefeld and Rolando variants, MECP2 mutations are rarely found. Consequently, authors proposed to perform analysis for mutations in CDKL5 for Hanefeld variant and in FOXG1 for Rolando variant (Neul et al, 2010).

U.S. Preventive Services Task Force Recommendations

Genetic testing for RTS is not a preventive service.

Billing/Coding/Physician Documentation Information

g/Coding/Physician Documentation Information This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81302, 81303, 81304, 81404, 81405, 81406

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Andrew S Davis, Handbook of Pediatric Neuropsychology; Oct 25, 2010.

Archer H, Evans J, Leonard H, et al. Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation. J Med Genet. Feb 2007;44(2):148-152. PMID 16905679

Christodoulou J, Ho G. MECP2-Related Disorders. 2001 Oct 3 [Updated 2012 Jun 28]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1497/

Jeffrey l. Neul, JL; Kaufmann, Walter E.; Glaze, Daniel G.; Christodoulou, John; Clarke, Angus J.; Bahi-Buisson, Nadia; Leonard, Helen; Bailey, Mark E. S.; Schanen, N. Carolyn; Zappella, Michele; Renieri, Alessandra; Huppke, Peter; Percy, Alan K.; Rettsearch, Consortium (2010). "Rett syndrome: Revised diagnostic criteria and nomenclature". Annals of Neurology. 68 (6): 944–50; link, link

Knight VM, Horn PS, Gilbert DL, Standridge SM. The Clinical Predictors That Facilitate a Clinician's Decision to Order Genetic Testing for Rett Syndrome. Pediatr Neurol. 2016 Jun 30. pii: S0887-8994(16)30061-3. doi: 10.1016/j.pediatrneurol.2016.06.016

Liyanage VR, Rastegar M. Rett syndrome and MECP2. Neuromolecular Med. Jun 2014;16(2):231-264. PMID 24615633

Lotan M, Ben-Zeev B. Rett syndrome. A review with emphasis on clinical characteristics and intervention. Scientific World Journal. 2006;6:1517-1541. PMID 17160339

Michelson DJ, Shevell MI, Sherr EH, et al. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. Oct 25 2011;77(17):1629-1635. PMID 21956720

Moeschler JB, Shevell M, Saul RA; Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014;134(3):e903– e918.

National Institute of Neurological Disorders and Stroke (NINDS), NIH, http://www.ninds.nih.gov/disorders/rett/detail_rett.htm

Neul JL, Kaufmann WE, Glaze DG, et. al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. Dec 2010;68(6):944-950. PMID 21154482

Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. May 2013;15(5):399-407. PMID 23519317

Suter B, Treadwell-Deering D, Zoghbi HY, et. al. Brief report: MECP2 mutations in people without Rett syndrome. J Autism Dev Disord. Mar 2014;44(3):703-711. PMID 23921973

Villard, L. (2007). MECP2 mutations in males. Journal of Medical Genetics,44(7), 417–423. http://doi.org/10.1136/jmg.2007.049452

Weaving LS, Williamson SL, Bennetts B, et al. Effects of MECP2 mutation type, location and Xinactivation in modulating Rett syndrome phenotype. Am J Med Genet A. Apr 15 2003;118A(2):103-114. PMID 12655490

Web MD website accessed Nov 15, 2016; IV.%09Evidence-based%20Scientific%20References

Williamson SL, Christodoulou J. Rett syndrome: new clinical and molecular insights. Eur J Hum Genet. Aug 2006;14(8):896-903. PMID 16865103

Policy Implementation/Update Information

1/1/2019 BCBSNC will provide coverage for genetic testing for Rett syndrome when it is determined to be medically necessary because criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)