Fetal and Pediatric Pathology, 32:375–383, 2013Copyright C© Informa Healthcare USA, Inc.ISSN: 1551-3815 print / 1551-3823 onlineDOI: 10.3109/15513815.2013.799249

ORIGINAL ARTICLE

Absent Sella Turcica: A Case Report and A Review ofthe Literature

Viktoriya Paroder,1 Todd Miller,1 M. Michael Cohen, Jr.,2

and Alan Lawrence Shanske3

1Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine,Bronx, NY, USA; 2Department of Pediatrics, Faculty of Medicine, Dalhousie University,Halifax, Nova Scotia, Canada; 3Children’s Hospital at Montefiore, Albert Einstein College ofMedicine, Bronx, NY, USA

Absent sella turcica is an extremely rare and dramatic radiographic finding. It may be isolated oroccur in the presence of other anomalies, often involving the adenohypophysis. Our evaluation ofa female infant with multiple anomalies including absence of the sella turcica, a normal pituitaryin the craniopharyngeal canal, normal pituitary function, choanal atresia and anomalies of theappendiceal skeleton prompted a review of the occurrence and biology of an absent sella turcica.

Keywords: sella turcica, adenohypophysis, choanal atresia, multiple anomalies

INTRODUCTION

A close relationship exists between the normal development of the central nervoussystem and its derivatives and the prenatal human cranium [1]. This rule applies aswell to the growth of the pituitary gland whose development originates from two sepa-rate anlage. Early in development a diverticulum of ectodermal tissue called Rathke’spouch grows upward from the roof of the mouth. This tissue is the precursor of theanterior pituitary or adenohypophysis. Recently, a mouse adenohypophysis was cul-tured from stem cells in vitro, with sonic hedgehog, bone morphogenetic proteinsand fibroblast growth factors added to the culture [2, 3]. These three factors are alsonecessary for normal development of the human adenohypophysis [4]. At the sametime in development, a second extension of ectodermal tissue, which will become theposterior pituitary or neurohypothysis, invaginates downward ventrally from the dien-cephalon of the brain. As these two tissues grow, they become very closely opposed butdo not lose their integrity, retain distinct functionality and can always be distinguishedbased on their histological characteristics. The sella turcica houses the pituitary gland.This is visible on radiographs and MRIs. It is not surprising then that extremes of pi-tuitary growth abnormalities are associated with abnormalities of the sella as in pitu-itary tumors (overgrowth) or the empty sella syndrome (hypoplasia). It must also be

Received 12 December 2012; Revised 3 April 2013; accepted 5 April 2013.Address correspondence to Dr. Alan Lawrence Shanske, M.D., Children’s Hospital at Montefiore,Albert Einstein College of Medicine of Yeshiva University, 3415 Bianbridge Avenue, Bronx, NY10467, USA. E-mail: ashanske@aol.com

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appreciated that there is even significant variation in the size and morphology of thesella in normal individuals [5].

The sella turcica (literally Turkish chair) is a midline, shallow depression in the pos-terior sphenoid bone that contains the pituitary gland. The roof of the sella turcica isformed by a dural reflection, the diaphragma sellae. The sella turcica is bounded an-teriorly by the tuberculum sella, and posteriorly by a prominent quadrilateral plate ofbone called the dorsum sellae. The anterior and posterior clinoid processes surroundthe sella turcica like the four corners of a four poster bed. The clivus is a shallow de-pression behind the dorsum sella that slopes obliquely backward and downward tobecome continuous with the basilar groove of the occipital bone.The basicranium (orskull base) provides support and protection to the intracranial contents at the bottomof the skull and serves as a passageway for many neural and vascular structures. Theskull base is called chrondrocranium, because many of its bones are first formed ascartilage and then ossify by the process of endochondrial ossification with little contri-bution from membranous bone. This ossification always happens in a specific orderlypattern but is not always at the exact same gestational age. It begins at the occipitalbone and proceeds to the posterior sphenoid and presphenoid portions of the sphe-noid and then to the ethmoid bone.

As opposed to the rest of the skull bones, which expand rapidly secondary to braingrowth, the basicranium grows a lot slower. Initially the pituitary is contained in thecartilaginous sella turcica of the basisphenoid. Ossification occurs from the posteriorto the anterior end of the sphenoid and first appears around the sella around 13 weeksand 5 days of development. There are four ossification centers that are involved indevelopment of the pituitary bed. The two medial ossification centers ossify first andsurround the pituitary to form the sella turcica. These may fuse or persist as two sep-arate ossification centers early in life. The lateral ossification centers ossify next. Thepresphenoid, which forms the body of the sphenoid bone anterior to the sella, ossi-fies in the region of the chiasmatic sulcus at around 17 weeks and 4 days. Subsequentprogressive ossification of the basiocciput, basispehnoid and presphenoid happens ataround 24 weeks and 4 days.

We recently examined an infant with an absence of the sella turcica, a normal pi-tuitary in the craniopharyngeal canal, normal pituitary function, choanal atresia andanomalies of the appendiceal skeleton. The absence of the sella, as opposed to a sizeor morphologic variant is a unique finding. A review of the literature did not reveal asingle published case of absence of the sella. We also attempted to classify this patternof anomalies using a combination of the 2010 revision of the Nosology of the Consti-tutional Disorders of Bone [6] and a review of the molecular correlates of bone mor-phogenesis [7] and concluded that this case may represent a unique syndrome.

CASE REPORT

The patient was born full term via crash C-section secondary to nonreassuring fetalheart testing during spontaneous vaginal delivery. Birth weight was 2855 gm (10–25thcentile). Family history was negative for consanguinity, fetal wastage, birth defects orneurologic diseases. The patient experienced immediate respiratory distress on de-livery and was intubated with resultant Apgars of 7 and 8 within a few minutes. MRIimages obtained on the second day of life demonstrated bilateral watershed area in-farcts, intraventricular hemorrhage and absence of dorsum sellae (Figure 1). CT im-ages also demonstrated bilateral choanal atresia for which the patient has undergonethree repairs. Additionally, incomplete ossification of the skull base was noted. Herphysical examination at 8 months revealed a mildly dysmorphic macrocephalic infantwhose weight was 5.5 kg (�5th centile) and head circumference 45.5 cm (95th centile)

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Absent Sella Turcica: A Case Report and A Review of the Literature

FIGURE 1 Reconstruction from the noncontrast CT (a) in sagittal plane and sagittal T2-weightedMRI (b) images demonstrates the absence of dorsum sellae (arrows). A normal appearing pituitarygland is visualized (∗).

(Figure 2). The forehead was broad, the flat nasal bridge, the pinna were normallyshaped and positioned and the palate was intact. The external auditory canalswere tortuous. She had hypertelorism with an inner canthal distance of 32.5 mm(�97th centile) and an outer distance of 77.9 mm (90th centile) and epicanthal folds(Figure 3). The neurologic examination revealed early muscle atrophy, involving the

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FIGURE 2 AP view of infant at 8 months showing broad forehead, flat nasal bridge hypertelorismand epicanthal folds.

lower extremities more than upper, poor truncal strength, hypotonia, inability to pickup head from prone position and very delayed developmental milestones. The patientwas tracheostomy dependent despite three attempts of repair.

Imaging of the lower extremities done because of apparent bowing of the left tibiademonstrated absent left fibula, hypoplastic right fibula and undertubulation of theleft tibia, which is roughly 1 cm shorter than the right tibia (Figure 4).

Initial echocardiogram at 7 weeks demonstrated patent foramen ovale and possiblesmall ventricular septal defect with normal left ventricular systolic function. Subse-quent echocardiogram at approximately 5 months demonstrated no significant ven-tricular septal defect. During the first month of life, a right femoral vein deep venousthrombosis was diagnosed and she was determined to be homozygous for MTHFR(C6777T). The protein S, methylmalonic acid and homocysteine levels were withinnormal limits.

Ophthalmologic evaluation demonstrated narrow optic nerves and no colobomas.Initial audiology evaluation was within normal limits. Due to feeding difficulties, up-per gastrointestinal series was performed and demonstrated no evidence of malro-tation. At 5 months of age, secondary to poor weight gain, a gastrostomy tube wasplaced after a videofluoroscopic study of swallowing showed there was evidence ofcricopharyngeal dysfunction and continued upper airway obstruction. She is now alsotracheostomy dependent.

Cytogenetics analysis of peripheral blood revealed an apparently normal femalechromosome complement. Pituitary function was evaluated with all the hormonal lev-els (including follicle stimulating hormone, luteinizing hormone and prolactin) withinnormal limits except for low insulin growth factor (IGF) (less than 25 ng/ml with thenormal range being 25–265 ng/ml). Thyroid function tests were within normal limits.

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Absent Sella Turcica: A Case Report and A Review of the Literature

FIGURE 3 Three-dimensional surface shaded reconstruction of MRI done at 61 weeks showing in-creased inner and outer canthal distances.

At 6 12 months repeat brain imaging was performed and demonstrated prominence

of the ventricles, underdevelopment of white matter particularly in the parietal andtemporal lobes, marked thinning of the corpus callosum and slightly small brain stem.The cerebrospinal fluid flow study was unremarkable and a ventriculoperitoneal shuntcatheter was placed.

Whole Genome Array CGHWhole genome array comparative genomic hybridization (CGH) was performed usingthe custom designed Agilent 44 k microarray (Agilent, Santa Clara, CA). The array con-tains 44 000 oligonucleotide probes. The probe density at clinically relevant regions,including sub-telomeres and microdeletion/duplication regions, is about 5–10 kb.Probes were placed about every 50–100 kb across the entire euchromatic genome toestablish a chromosomal backbone with a resolution of approx 500 kb, which is in-creased to approx 50 kb resolution in targeted regions based on hg18. No major aber-rations were detected.

DISCUSSION

In our patient, the development of the pituitary gland appears intact as shown bythe presence of a normal appearing pituitary gland on imaging as well as normal en-docrine laboratory lab values. Restudy of the MRI indicated that the pituitary glandrests within a fossa on the surface of the cranial base, but without the clinoid processes(Figure 1). In MRIs that were ordered for pathological purposes, the appearance in Fig-ure 1 was found once in approximately 500 MRI patients [8].

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FIGURE 4 (a) AP radiograph of lower extremities showing absent left fibula (∗), left tibia 1 cmshorter than the right tibia. (b) Lateral radiograph of right leg shows hypoplastic right fibula (ar-row). (c) Lateral view of left leg shows undertubulated (absence of normal physiologic narrowing oflong bone diaphysis) tibia and absent fibula.

In the 2010 revision of the Nosology and Classification of Genetic Skeletal disor-ders, 456 conditions were included and placed in 40 groups defined by molecular, bio-chemical and/or radiographic criteria [6]. Of these conditions, 316 were associatedwith mutations in one or more of 226 different genes, ranging from common, recur-rent mutations to “private” ones found in single families or individuals [6]. We turnedto the Nosology as a useful clinical tool for delineating newly described clinical en-tities awaiting confirmation of their phenotypic spectrum by molecular clarification.Similarly, we reviewed the molecular correlates of the bony pathology without suc-cess. However, the major bone involvement in our patient is of the sella turcica, thechoanae and the tibia and fibulae suggesting a dysostosis, provisionally a unique pat-tern syndrome. Dysostoses are disorders affecting individual bones or group of bones.

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Absent Sella Turcica: A Case Report and A Review of the Literature

The dysostoses often arise from embryonic morphogenic defects and are more likely tobe associated with a multiple malformation syndrome such as our case. Among the 40groups listed in the Nosology and Classification of Genetic Skeletal Disorders includedare two dysostosis groups. We could not find a disorder within groups 34 (dysostosiswith predominant craniofacial involvement) and 38 (limb hypoplasia-reduction de-fects) that resemble the phenotype of our patient.

Choanal atresia is a major finding in our patient and suggests the CHARGE asso-ciation that is not included in the Nosology and Classification. Harris et al. [9] deter-mined that a weak, nonrandom association can be demonstrated between the mal-formatilons of the CHARGE association. However, only 7% of infants studied withthree or more malformations belonged to the CHARGE association. He concludedfor the diagnosis of CHARGE to apply, it must be restricted to infants with choanalatresia and/or coloboma with other cardinal malformations. Verloes et al. [10] pro-posed an updated version of diagnostic criteria for CHARGE syndrome. Nagase [11]cloned CHD7 (OMIM#608892) and sequenced the CHD7 gene in 110 individuals whohad received a clinical diagnosis of CHARGE syndrome and detected mutations in64 (58%). Nagase sequenced a second gene, SEMA3A, mutated in some patients withthe CHARGE association [12]. Our patient does not fulfill the clinical criteria for theCHARGE association and although sequencing of CHD7 was not done it is interest-ing to note that Sanlaville et al. [3] analyzed the expression pattern of the CHD7 geneduring early human development and found that CHD7 is widely expressed in undif-ferentiated neuroepithelium and in mesenchyme of neural crest origin [13]. In em-bryological development, the sella turcica area is a key point for the migration of theneural crest cells to the frontonasal and maxillary developmental fields [1]. However,no abnormalities of the sella to our knowledge have been reported in the CHARGEassociation.

A number of syndromes are associated with changes in the morphology of the sellaturcica but not the total absence including Nelson syndrome [14], Gorlin syndrome[15], Rieger syndrome [16], holoprosencephaly [17], trisomy 18 [18], myelomeningo-cele [19], Down syndrome [20], cri-du-chat [21], solitary median maxillary central in-cisor (SMMCI) [22], Seckel syndrome [23], Williams syndrome [24] and cleft palate[25]. A number of classifications have been devised to qualify and quantify these vari-ations [26]. Some of these syndromes are characterized chiefly by changes in theanterior wall (Down syndrome, myelomeningocele, Williams syndrome (female), andNelson syndrome). Bridging is a characteristic finding in Gorlin syndrome, in se-vere craniofacial deviations and in SMMCI. Changes in the dorsum sellae are seen inthe cri-du-chat, Rieger and Williams syndromes. Changes in the anterior wall andthe dorsum sellae are observed in cleft lip and palate. Many of these same vari-ations are seen in the sella of normal individuals [26–28]. A long shallow sellaturcica has been described in 23/25 cases in the literature of patients with Muli-brey (MUscle, LIver, BRain and EYes) nanism (“dwarfism”), which is caused bymutation the TRIM37 gene (OMIM#605073), which encodes a peroxisomal protein[29].

A number of studies have shown that cranial base angles are increased in individu-als with the velocardiofacial syndrome (VCFS) [30, 31]. Molsted et al. confirmed theseearlier findings and described deviations in the posterior part of the dorsum sellae[32]. This finding was described as a new sign in the VCFS phenotype, which should beadded to the anomalies described in the VCFS. It is perhaps not surprising that a sec-ond abnormality of the cranial base should be identified in this disorder. The cranialbase angle is normal in our patient. Phenotypic studies of Tbx1-null mouse mutantshave substantiated the role of Tbx1 in the etiology of all of the physical anomalies inthe 22q11 deletion syndrome [33].

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Meyer-Marcotty assumed that a sella bridge in combination with a prominent pos-terior clinoid process followed by a steep clivus is a distinct feature of Axenfield-Riegersyndrome caused by PITX2 mutation (OMIM#601542). [34]. PITX2 is expressed in theRathke pouch and limb mesenchyme [35]. The sella turcica was malformed in the twofetuses with fragile X syndrome. One had deep notching in the anterior wall and theother a very short dorsum sellae. In one fetus, a notochordal tissue remnant was seenin the dorsum sellae with an irregular course [36].

The sella turcica marks the cranial extent of the notochord embryologically. The no-tochord has an influence on the development of the pituitary gland and the brain andmay also have an influence on the release and migration of neural crest cells [32]. Thedeviations in the posterior part of the sella and enlarged cranial base angulations inVCFS further support the hypothesis that abnormalities of sella morphology or de-velopment may be secondary to genes such as CHD7 that are vital for neural crestmigration, epithelial–mesenchymal interactions or cell condensation. The moleculargenetic analysis of skeletal syndromes has resulted in the refinement of diagnostic ac-curacy and the identification of new disorders [6]. Microarray analysis revealed no du-plications or deletions across the whole genome in our patient. The importance of themolecular correlates of bone and cartilage formation to our understanding of theirpathogenesis has been reviewed by Cohen [7]. However, no sequence information isavailable from our patient. Sequencing of candidate genes such as CHD7, SEMA3E,PTX2 and TBX1 with demonstrated roles in neural crest growth, migration or devel-opment would be especially helpful and will be part of our future evaluation of thispatient. In the interim, the description of an absent sella turcica in our patient, an un-usual and rarely reported finding, will stimulate additional observations and research.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for thecontent and writing of this article.

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