Genetic dissection of Chiari malformation type 1 using endophenotypes and stratification

Aintzane Urbizu1, Tahir N. Khan2, Allison E. Ashley-Koch1*

1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA
2Duke Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA

 Chiari malformation type 1 is a heterogeneous disease characterized by cerebellar tonsillar herniation through the foramen magnum. Symptomatology is diverse, and diagnosis and treatment are controversial. Some evidence suggests the presence of a genetic component to the disease. However, the specific genetic factors involved remain relatively unknown. Previous reviews have broadly addressed different aspects (clinical manifestations, anatomical trails, treatment) of CM-1 by itself or compared it with other types of Chiari malformation. In this mini-review, we focus our attention on the heterogeneity of this disease and its impact on the study of the genetic etiology of classic CM-1. Patient stratification strategies and endophenotypes definitions are offered to help overcome the heterogeneity.


Chiari malformation type 1 (CM-1) is the most prevalent form of the “Chiari malformations”, and is characterized by a downward herniation of the caudal part of the cerebellum through the foramen magnum into the upper cervical region (Figure 1). It is a very heterogeneous disease whose current diagnosis relies on an imaging observation of cerebellar tonsil herniation (TH) of at least 3-5mm below the foramen magnum1,2. This TH is usually attributed to a reduced size of the posterior cranial fossa (PCF) (classic CM-1), although other mechanisms may be involved (see below). That is, the subsequent smaller cranial space leads to overcrowded neural structures and the herniation of the cerebellum through the foramen magnum. This results in a direct compression of the neural tissue at the craniovertebral junction and, often, cerebrospinal fluid (CSF) disturbances (decreased velocity and elevated impedance), that can cause other related conditions such as syringomyelia or secondary hydrocephalus3,4.


Figure 1

Sagittal T1W1 MRI showing the PCF in four different adult women. In A) Control, B) Classic CM-1 patient with a short basioccipital bone, reduced clivus slope and smaller tentorium angle, C) Classic CM-1 patient with a short supraoccipital bone and smaller tentorium angle, and D) Classic CM-1 patient with a short basioccipital bone, reduced clivus slope and bigger tentorium angle. Cerebellum tonsillar herniation (TH) is showed in magenta in B. The occipital bone is shown in green: basioccipital (BO, from 2 to 3) and supraoccipital (SO, from 4 to 5). Basisphenoid (BS, from 1 to 2) with basioccipital results in the clivus (from 1 to 3). The asterisk shows the shorter occipital part in each patient. Tentorium angle (TA) is given by the tentorium cerebelli (from 5 to 6) and supraoccipital bone. Basal angle (BA) > 143º is considered platybasia.

CM-1 is quite heterogeneous with respect to symptomatology, epidemiology and treatment. The symptomatology presented by CM-1 patients is diverse, and its severity does not correlate with the degree of TH, with some asymptomatic cases presenting with prominent TH3,5.. The onset of symptoms generally develops gradually, however, trauma, coughing/sneezing or pregnancy can also precipitate the event3,6,7. The incidence, prevalence and distribution of CM-1 is still unclear, and estimations vary depending on the criteria used to characterize the disease: TH criterion alone, TH criterion accompanied by symptomatology or a defining mechanism of the TH. For example, in the United States (US), almost 1 % of normal adults undergoing MRI scanning have at least 5mm of TH but only about 0.01–0.04 % of adults demonstrate symptoms of CM-18. Epidemiological data from other countries is generally missing. Moreover, in the US, estimates of the prevalence based on specific subtypes and/or comorbid conditions are scarce. Thus, the true prevalence of the condition, with respect to all forms of clinical heterogeneity is unknown. The treatment varies depending on the etiology of the TH. Indeed, in classic CM-1 it also depends on the severity of symptoms, the degree of TH and the presence of other conditions (i.e. syringomyelia or scoliosis). The most common treatment for these patients is surgical PCF decompression (alone or with duraplasty), although cerebellar tonsillectomy, cervical laminectomy, suboccipital cranioplasty are also applied9,10. The goal of these surgical procedures is to decompress the foramen magnum and increase the subarachnoid space in order to avoid the impaction of the cerebellar tonsils, reestablish the CSF flow and reverse the symptoms. However, there is still not a consensus about the best procedure to follow, since not all surgeries result in improvement of symptoms and often more than one surgery is required8.

The presence of multiplex families with several CM-1 cases, the co-occurrence of CM-1 in monozygotic twins and the co-inheritance with known genetic syndromes (Table 1) strongly argue for a genetic contribution to CM-1 pathogenicity11. Despite this evidence, the precise genetic variants causative of the disease remain elusive in most cases. Several genetic studies, using different approaches (mutational analysis, whole genome linkage analysis, genetic association, expression analysis) have been performed in order to attempt to identify the genetic traits underlying this disease11-16. This work has resulted in the implication of several chromosomal regions and a number of candidate genes (Table 2). However, it is important to highlight that the major findings were achieved when the CM-1 population was stratified and analyzed in more homogenous clinical groups.

Table 1. Genetic disorders which can co-occur with CM-1.
Disorder or Syndrome Associated clinical anomalies Chromosome location (gene) OMIM Inheritance model Reference
Achondroplasia Skeletal 4p16.3 (FGFR3) #100800 AD & sporadic 35
Acromegaly Endocrine 20q13.32 (GNAS) #102200 Unknown 36-38
Blepharophimosis Ophthalmic 3q23 (FOXL2) #110100 AD 39
Bone marrow failure syndrome 1 Hematologic 4q12 (SRP72), #614675 AD & AR 40
  9q22 (ERCC6L2) #615715  
Cleidocranial dysplasia Skeletal 6p21.1 (RUNX2) #119600 AD 41
Craniometaphyseal dysplasia Skeletal 5p15.2 (ANKH), #123000, AD & AR 42
  6q22.31 (GJA1) #218400  
Cystic fibrosis Exocrine 7q31.2 (CFTR) #219700 AR 43-45
Epilepsy Neurologic 8q24 %600131 AD 46
Fanconi anemia Hematologic 16q24.3 (FANCA) #227650 AR 47
Furhmann syndrome Skeletal, dermatologic & endocrine 3p25.1 (WNT7A) #228930 AR 48
Goldenhar syndrome Skeletal 14q32 %164210 AD 49
Growth hormone deficiency Endocrine 17q23.3 (GH1) #262400 AD, AR & X-linked 50-54
  Xq22.1 (BTK) #173100  
Hajdu–Cheney syndrome Skeletal 1p12 (NOTCH2) #102500 AD 55
Hyper IgE syndrome Immune 17q21.2 (STAT3) #147060 AD 56
Hypophosphatemic rickets Skeletal Xp22.2-p22.1 (PHEX) #307800 X-linked 57, 58
Kabuki syndrome Miscellaneous (FF, ID, skeletal, etc.) 12q13.12 (KMT2D) #147920 AD 59, 60
Klippel-Feil syndrome Skeletal 8q22.1 (GDF6), #118100 AD, AR & sporadic 3, 24, 61
  17q21.31 (MEOX1), #214300  
  12p13.31 (GDF3) #613702  
Leopard syndrome Miscellaneous (dermatologic, etc.) 12q24.13 (PTPN11) #151100 AD 62, 63
Neurofibromatosis type I Dermatologic 17q11.2 (NF1) #162200 AD 64-70
Noonan syndrome Miscellaneous (skeletal, FF, etc.) 12q24.13 (PTPN11) #163950 AD 71
Osteopetrosis Skeletal 11q13.2 (LRP5), #166600, AD, AR & X-linked 72-74
  13q14.11 (TNFS11), #611490  
  16p13.3 (CLCN7) #607634  
Paget disease of bone Skeletal 18q22.1 (TNFRSF11A), #602080 AD & AR 75, 76
  5q35 (SQSTM1), #167250  
  5q31 (PDB4) %606263  
  8q24.12 (TNFRSF11B) #239000  
  1q21.3 (ZNF687) #616833  
Pseudohypoparathyroidism type 1A Endocrine 20q13.32 (GNAS) #103580 AD 77
Renal-coloboma syndrome Ophthalmic & renal 10q24.3-q25.1 (PAX-2) #120330 AD 78
Rubenstein-Taybi syndrome Miscellaneous (ID, skeletal, FF, etc.) 16p13.3 (CREBBP), #180849, AD & sporadic 53, 79, 80
  22q13.2 (EP300) #613684  
Scoliosis Skeletal 19p13.3, %181800 AD 81-85
  17p11.2 %607354  
  8q12 %608765  
  9q31.2-q34.2 %612238  
Severe combined pituitary hormone deficiency Endocrine 3p11.2 (POU1F1), #613038 AD & AR 53
  5q35.3 (PROP1), #262600  
  9q34.3 (LHX3), #221750  
  1q25.2 (LHX4) #262700  
Spondylo-epiphyseal dysplasia tarda Skeletal Unknown #271600 AD, AR & X-linked 86
Townes-Brocks syndrome Skeletal & gastrointestinal 16q12.1 (SALL1) #107480 AD 87
Velocardiofacial syndrome Miscellaneous (skeletal, neurologic, etc.) 22q11(TBX1) #192430 AD 88
William's syndrome Miscellaneous (ID, FF, cardiovascular, etc.) 7q11.2 (Deletion of aprox 28 genes including: LIMK1, RFC2, WBSCR1, WBSCR2) #194050 AD 89, 90

AD: autosomal dominant inheritance, AR: autosomal recessive inheritance, FF: facial features, ID: intellectual disability

Table 2. List of the candidate genes suggested for CM-1 from genetic studies performed.


Gene OMIM Encodes for / Involved in Type of study Reference
1p36 RUNX3 *600210 Transcription factor / Segmentation body in Drosophila Expression 16
1q25.2 LHX4 *602146 Transcription factor / Differentiation & development of pituitary gland Linkage analysis 20
3p21.31 PTH1R *168468 Receptor parathyroid hormone & parathyroid hormone / Chondrodysplasias & enchodromatosis Expression 16
3p22 TGFBR2 *190182 Transmembrane protein / Transcription genes related cell proliferation Expression 16
3p22-p21.2 RPL14   Ribosomal protein eQTL 15
3q26.2 RPL22L1   Ribosomal protein eQTL 15
5q14.2 RPS23 *603683 Ribosomal protein eQTL 15
5q32 CDX1 *600746 Transcription factor / Anterior-posterior regional identify Association 13
6p21 RUNX2 *600211 Transcription factor / Osteoblastic differentiation & skeletal morphogenesis Expression 16
6p21.3 NOTCH4 *164951 Transmembrane protein / Chondrocyte Proliferation & maduration Expression 16
8q12 RPS20 *603682 Ribosomal protein eQTL 15
8q22.1 GDF6 *601147 Member of BMP family and the TGF-beta superfamily/ Bone formation Linkage analysis 14
9q34.3 NOTCH1 *190198 Transmembrane protein / Proliferation & maduration of chondrocytes Expression 16
11q23.3 ETS1 *164720 Transcription factor / Osteoblast differentiation & bone formation Expression 16
12p11.21 IPO8 *605600 Ras-related small GTP-binding protein / Osteoblast differentiation eQTL 15
12p13.31 GDF3 *606522 Ligand of TGF-beta protein / Ocular & skeletal development Linkage analysis 14
Klippel-Feil syndrome Skeletal 8q22.1 (GDF6), #118100 AD, AR & sporadic 3, 24, 61
12q13 RPS26 *603701 Ribosomal protein eQTL 15
12q13.11 COL2A1 +120140 Collagen / Cartilage & the vitreous humor of the eye Expression 16
13q12 FLT1 *165070 Receptor tyrosine kinases / Angiogenesis & vasculogenesis Association 13
14q21 RPL36AL *180469 Ribosomal protein L36A-like eQTL 15
15q21.3 ALDH1A2 *603687 Aldehyde dehydrogenase protein / Mesoderm differentiation & somitogenesis Association 13
15q21.1 FBN1 *134797 Mature extracellular matrix glycoprotein / Connective tissue Linkage analysis 12
16p12.3 XYLT1 *608124 Xylosyltransferase enzyme / Ossification eQTL 15
17q24.2 PRKAR1A *188830 Protein kinase / Associated with genetic disorder of bone growth eQTL 15
21q22.2 ETS2 *164740 Transcription factor / Osteoblast differentiation & bone formation Expression 16
22q13.1 ATF4 *604064 Transcription factor / Osteoblast differentiation Linkage analysis 20
22q13.2 EP300 *602700 Histone acetyltransferase / Cell proliferation & differentiation Linkage analysis 20

In a heterogeneous condition like CM-1, it is essential to properly characterize the patients, not only to establish a good diagnosis, but also to decide the best treatment to follow and to perform studies that help to improve the etiologic knowledge of the disease. Although TH is widely used in the diagnosis of CM-1, it is not heritable or completely correlated with symptomatic disease12,16. Since TH seems to be secondary in CM-1, other factors should be considered in order to successfully identify the genetic etiology of CM-1.

As mentioned above, it has been generally assumed that TH was a consequence of a hypoplasic PCF due to a shortening of the occipital bone caused by an insufficiency during paraxial mesoderm development17. However, other cranial constriction mechanisms, such as premature closure of the cranial sutures (craniosynostosis), can also produce a reduced PCF with a smaller occipital bone; in addition, the reduced PCF is not the only explanation for the origin of TH. Other mechanisms such as cranial settling, occipitoatlantoaxial joint instability, spinal cord tethering, intracranial hypertension and intraspinal hypotension, can lead to TH18. For some of these mechanisms, different causal genetic pathways have been described. For example, craniosynostosis with TH (OMIM: #101200, #304110, #123500, #101600, #182212) can be produced by mutations in the FGFR1, FGFR2, EFNB1 and SKI genes; and connective tissue disorders with TH (OMIM: #601776, #615539, #609192, #610168, #613795, #615582, #154700) have been associated with mutations in the DSE, CHST14, TGFBR1, TGFBR2, SMAD3, TGFB3 and FBN1 genes.

In classic CM-1, most candidate genes have been related to the different stages of occipital bone development, including the paraxial mesoderm development, somite and sclerotome formation, chondrogenesis and osteogenesis (Table 2)13,15,16,19,20.

Stratifying according to the TH mechanism (presence or absence of history of connective tissue disorders), Markunas et al. observed that the evidence for genetic linkage in several chromosomal regions increased significantly and led to the identification of two missense mutations with incomplete penetrance in the GDF6 gene in two independent classic CM-1 families14 (Table 2).

Although TH herniation is not heritable12,16, other PCF traits are, and the use of these heritable traits are more likely to aid in the identification of the underlying genes.

PCF morphometric characteristics are different in CM-1 patients according to the mechanism of TH18. In addition, although a hyploplastic PCF is a common trait for classic CM-1 patients, the regions of the PCF are not equally affected16,13,20. Usually the PCF is shallower, as a result of the shorter occipital bone, and often the slope of the clivus is reduced, resulting in a predisposition to platybasia. Most studies demonstrated the basilar part of the occipital bone (basioccipital) or clivus (when the sphenoccipital synchondrosis is not visible) is significantly reduced6,21,22. However, for some cohorts this reduction seems to be more significant in the supraoccipital part23,24, or present for both regions4. There are also conflicting reports about the magnitude of the tentorium angle in patients compared to control cohorts3,22 (Figure 1).

Since the formation and development of the occipital bone is intricate, a morphometric analysis of the PCF based on MRI is essential in classic CM-1 patients. Depending on which part of the occipital bone is abnormal (shorter and/or present with different slope), the genes involved may be different. The occipital bone is formed from the fusion of the first four somites. However, the parts of these somites that resegment to form the sclerotomes are different for each part of the bone25. The basilar part fuses with the basisphenoid bone at the sphenoocipital synchondrosis (which derives from neural crests cells and the mesoderm, and its closure finishes at the age of 20 years)8; but the boundaries of the supraoccipital part are given by the interparietal-supraoccipital, lamboid and occipito-mastoid sutures8,26. In addition, the occipital bone has both membranous and cartilaginous types of ossification, and the number of ossification centers for each part is different8,26.

After considering the PCF traits presented in CM-1 patients, Urbizu et al. identified four genetic variants (located in the genes ALDH1A2, CDX1 and FLT1) to be associated with adult classic CM-1, and two of them also associated with the slope of the clivus31(Table 2). Using MRI endophenotypes defining two different “shapes” of PCF, Markunas et al. identified different levels of expression in genes related with dorso-ventral axis formation (ETS1, ETS2, NOTCH4), ribosome, spliceosome and proteasome in pediatric classic CM-1 patients16 (Table 2). These initial findings support the complex genetic basis of the PCF development, and the genetic heterogeneity of CM-1.

Another approach to identifying genes for CM-1 is to stratify CM-1 according to co-occurring genetic disorders, either by syndrome or according to the associated clinical anomalies (skeletal, hematologic, ophthalmic, endocrine, exocrine, dermatologic, neurologic or immune) (Table 1). Importantly, some of these different disorders may be related since: 1) they are caused by the same gene/locus (i.e. mutations in GNAS gene have been identified in patients with acromegaly and Pseudohypoparathyroidism type 1A), 2) some of these genes interact (i.e. CREBBP and EP300 are genes that cause Rubenstein-Taybi syndrome, and are involved in chondrocyte differentiation; they interact with LHX4 which is associated with severe combined pituitary hormone deficiency, also described in CM-1 patients), and 3) some of these genes are in the same pathway (i.e. Noonan syndrome and Neurofibromatosis type 1 are caused by alterations in Ras pathway genes).

The majority of CM-1 cases are believed to be sporadic. However, familial cases (presenting autosomal recessive and autosomal dominant inheritance with incomplete penetrance) have also been reported12. Thus, it is possible that the presence or absence of family history is associated with different genes and disease pathogenesis. For example, in some diseases such as Fronto Temporal Dementia or Amyothropic Lateral Sclerosis, different genes, and even different pathways, are affected depending if the cases are familial or sporadic27. The fact that some CM-1 families present different inheritance patterns also suggests that there is more than one gene involved in the disease.

Traditionally, CM-1 has been considered an adult form of the Chiari malformations since the onset of the symptoms usually occurs during the second or third decade of life. More recently, because of the increased use of MRI diagnosis and clinical awareness, this perception is changing, with an increasing number of pediatric cases being reported10,28,29 . Both pediatric and adult CM-1 patients have TH in common. However, the symptomatology, comorbidities and gender proportion are not exactly the same. For example, and although the precise estimate is still unknown, in adults a higher incidence is generally observed for females, while in pediatric cases this incidence is more evenly distributed among sexes3,10,13,18, 19,30.These differences could indicate that pediatric and adult onset cases are different forms of the disease. There are many examples of other diseases where age of onset is important. In Alzheimer disease, different genetic variants are involved in the early (younger than 65 years old) and late onset forms of the disease31.

The fact that in CM-1 adult form is more common in females, suggests the possibility of sexual-dimorphism. Gender effects can manifest in the presentation of the disease, associated symptoms, prevalence, or age of onset. These differences are also seen in CM-1 as we have described above. Sexual-dimorphism has been observed in other complex human diseases such as cardiovascular disease, asthma, autoimmune diseases, some neurological and psychiatric disorders, as well as some common birth defects and cancers32. Many complex human diseases exhibit sex and age differences in gene expression where common variants may alter gene expression and influence disease susceptibility or its progression33. For CM-1, the alteration in the occipital bone could be produced at different developmental time points, from embryonic stages until the completion of bone development. Importantly, hormones (parathyroid hormone, growth hormone), including sexual hormones (estrogen, testosterone), are involved in bone growth34. Interestingly, some disorders that co-occur with CM-1 are caused by endocrine alterations (Table 1).

In conclusion, there remains little known about the genetic component involved in the etiology of CM-1. There is a tremendous need to replicate the published studies and validate the findings in independent cohorts, as well as to consider the effect of these stratification strategies on proposed candidate genes. We also cannot discard other genomic mechanisms, such as regulatory variation and epigenetic modifications, as additional contributors to disease etiology.

Thus, other genomic approaches may be needed, such as epigenetic analyses and next generation sequencing, which have not yet been applied to CM-1. Ultimately, however, a better understanding of meaningful clinical stratifications will be required to identify more genetically homogeneous subsets in order to find the causative genetic variants.

A.U. is the recipient of a Postdoctoral Fellowship from Fundación Ramón Areces (Spain). We would like to thank Conquer Chiari for providing the images in Figure 1.

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Article Info

Article Notes

  • Published on: March 10, 2017


  • Chiari malformation type 1

  • Posterior cranial fossa
  • Genetic component
  • MRI
  • Endophenotypes
  • Stratification


Dr. Allison E. Ashley-Koch
Professor, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, Tel: 1 (919) 684-1805; Fax: 1 (919) 684-0912