- Division of Neurosurgery, MetroHealth Medical Center, Cleveland, Ohio
- Department of Pediatrics, Division of Genetics, MetroHealth Medical Center, Cleveland, Ohio
Robert T. Geertman
Division of Neurosurgery, MetroHealth Medical Center, Cleveland, Ohio
DOI:10.4103/2152-7806.92939Copyright: © 2012 Manjila S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Manjila S, Miller EA, Vadera S, Goel RK, Khan FR, Crowe C, Geertman RT. Duplication of the pituitary gland associated with multiple blastogenesis defects: Duplication of the pituitary gland (DPG)-plus syndrome. Case report and review of literature. Surg Neurol Int 15-Feb-2012;3:23
How to cite this URL: Manjila S, Miller EA, Vadera S, Goel RK, Khan FR, Crowe C, Geertman RT. Duplication of the pituitary gland associated with multiple blastogenesis defects: Duplication of the pituitary gland (DPG)-plus syndrome. Case report and review of literature. Surg Neurol Int 15-Feb-2012;3:23. Available from: http://sni.wpengine.com/surgicalint_articles/duplication-of-the-pituitary-gland-associated-with-multiple-blastogenesis-defects-duplication-of-the-pituitary-gland-dpg-plus-syndrome-case-report-and-review-of-literature/
Background:Duplication of the pituitary gland (DPG) is a rare craniofacial developmental anomaly occurring during blastogenesis with postulated etiology such as incomplete twinning, teratogens, median cleft face syndrome or splitting of the notochord. The complex craniocaudal spectrum of blastogenesis defects associated with DPG is examined with an illustrative case.
Case Description:We report for the first time in the medical literature some unique associations with DPG, such as a clival encephalocele, third cerebral peduncle, duplicate odontoid process and a double tongue with independent volitional control. This patient also has the previously reported common associations such as duplicated sella, cleft palate, hypertelorism, callosal agenesis, hypothalamic enlargement, nasopharyngeal teratoma, fenestrated basilar artery and supernumerary teeth. This study also reviews 37 cases of DPG identified through MEDLINE literature search from 1880 to 2011. It provides a detailed analysis of the current case through physical examination and imaging.
Conclusion:The authors propose that the developmental deformities associated with duplication of pituitary gland (DPG) occur as part of a developmental continuum, not as chance associations. Considering the fact that DPG is uniquely and certainly present throughout the spectrum of these blastogenesis defects, we suggest the term DPG-plus syndrome.
Keywords: Blastogenesis, clival encephalocele, diprosopus, duplication of the pituitary gland, split notochord
Duplication of the pituitary gland (DPG) is an extremely rare malformation that has been described in fewer than 40 cases since 1880. Several mechanisms have been proposed for DPG: partial twinning, prenatal teratogen exposure, extreme presentation of the median cleft face syndrome or splitting of the notochord during blastogenesis.[
We present an eleven-year-old African-American female patient with multiple craniofacial anomalies that we speculate to have occurred during blastogenesis. She demonstrates duplication of both bony and soft tissue midline facial and cranial structures. Facial abnormalities include turribrachycephaly, flattened midface, hypertelorism, cleft palate, bilateral cleft lower lip, supernumerary teeth, macrostomia, short neck with limited range of movement and two separate, fully formed, independently moving tongues – double tongue [
The patient demonstrates severe intellectual disability; she is nonverbal and does not follow commands but does point to things she wants. Cranial nerves are difficult to assess on examination. Visual acuity could not be reliably tested. However, she is able to recognize people and objects. Cranial nerves III-VII are unremarkable, CNVIII demonstrates profound hearing loss, and cranial nerves X, XI, XII are normal except for volitional independent control of both tongues.
The patient has a thoracic scoliosis of 55 degrees. Her height is in the 3rd percentile, weight in the 10th and head circumference in the 25th percentile. She has thin lower legs, small narrow feet, and tight left heel cord. She moves all extremities spontaneously but strength can not be reliably tested. Spasticity of both lower extremities is also present, with reflexes of 2-3+ in both upper and lower extremities. She is unable to bear weight on her legs, but does crawl, scoot and support herself when sitting. She is able to assist with dressing by holding her arms up and spreading her legs for diaper changes.
The patient was born to a previously healthy 34-year-old G4P3 mother with a pregnancy complicated by failure of maternal weight gain and polyhydramnios noted during the last 2 weeks of gestation. Her mother denies medication use, drug or alcohol abuse. Early ultrasound did not reveal any abnormalities due to a large fibroid causing poor visualization of fetal parts. An ultrasound in the third trimester showed no gross deformities, but an absent lower lip. Three healthy older siblings show no similar abnormalities. Her parents are not consanguineous and there is no family history of malformations. The child was born via cesarean section due to fetal bradycardia at full term. Apgar scores were 4/7 and she was noted to have a mass in the anterior lower jaw, filling the oral cavity and extending into the posterior fossa. The mass prevented intubation but she responded to suctioning and chest compressions. She remained hypercapnic with a pCO2 of 81 necessitating a tracheostomy at 2 days of age. The intraoral mass was biopsied at this time and found to be a mature teratoma. A gastrostomy tube was placed soon after for feeding. Severe reflux necessitated a Nissen fundoplication after G tube placement.
An incomplete resection of the oropharyngeal tumor was performed at 15 months of age. The tumor originated on the posterior aspect of the mandible and extended posteriorly to the pharynx and superiorly into the nasal cavity to the level of the crista galli. It was completely intraoral; only retrognathia and cleft lip were visible exteriorly. Intra-operatively, the tumor was found to have prevented fusion of the palatal shelves, creating a cleft palate. It had also grown inferiorly, creating two completely separate tongues extending back to the foramen cecum; the double tongue, however, was not surgically corrected to monitor recurrence of the teratoma. Resection of the tumor necessitated removal of the alveolar ridge of the mandible and most of the nasal septum. Posteriorly, the dissection was stopped at the level of the cranial base to prevent surgical entry into the cranial cavity with the risk of subsequent CSF leak or infection. The final pathology of the tumor was mature teratoma. Residual tumor was left behind in the posterior fossa in the region of the clival encephalocele.
The past medical history is remarkable for multiple surgical interventions. Volvulus at age 7 required partial ileal and colon resection leading to short gut syndrome. She has also had soft tissue release and anterior tibial transfer performed on the left foot for a tight heel cord. The patient has a history of self-mutilation, including hand biting, scratching and hair pulling when she is upset, requiring frequent restraints. She has been home schooled due to infection risk.
Head MRI reveals duplication of multiple midline structures: two sellas and two pituitary glands, a duplicate ventricular system, two basilar arteries and a midline third cerebral peduncle [Figures
Karyotype from teratoma demonstrated normal chromosomes with 60:40 X inactivation. Telomeres were normal. A microarray based comparative genomic hybridization analysis of 3,397 loci using olignonucleotide probes was normal (Nimble Gen 135K).
Duplication of the pituitary gland (DPG) has been reported in the medical literature in both the pediatric and the adult population. Discussion of pituitary duplication warrants a brief review of the normal development of the hypophysis to vividly understand the process of duplication and associated anomalies.
Development of the pituitary gland
The development of the human hypophyseal, or pituitary gland, has been widely studied due to its complex origin from multiple tissues.[
Mesoderm under the influence of the hypothalamus accumulates on both sides of the pouch, further inducing its development. At 37 days gestation, the neurohypophysis grows out from the infundibular recess and folds influenced more by rapid growth in the area around the tissue than by mitotic activity within it. The connection of the adenohypophysis is severed in the seventh week by cartilage growth of the sphenoid and the gland loses all connectivity with the oral cavity. A remnant of the connecting stalk remains in the posterior nasopharynx, termed the pharyngeal pituitary. The connection of the neurohypophysis with the diencephalon remains throughout life. By the 8th week, the pituitary is nearing mature form as the sphenoid grows to envelop the gland, creating the pituitary fossa. Throughout the remainder of gestation, the gland finalizes its differentiation and blood supply.[
The prechordal plate has previously been shown to induce the development of the hypophysis; the adenohypophyseal plate is in early contact with the prechordal plate directly. The initial signaling in the induction is thought to be through homeobox factors.[
Duplication of the pituitary gland
Duplication of organs can arise from several developmental errors. Organs that form from two separate primordia may be duplicated from a failure of fusion. Those that form as a single entity require either a specific insult or a second induction signal to create duplication. Since the pituitary is formed from a single primordium, induction or insult must be considered when examining the cause of hypophyseal duplication.
Previously proposed theories for DPG include failed twinning,[
Morton (1956) proposed that DPG and the associated cranio-facial abnormalities could be explained by splitting of the notochord or prechordal plate at its rostral end. This would lead to the duplicate facial structures, such as bifid tongue, bifid uvula, supernumerary teeth, and nasal/palatal clefting observed in most cases of pituitary duplication; 22 of the 40 cases reviewed demonstrated midfacial defects [
Failed twinning was first proposed as an explanation of DPG by Ahlfeld in 1880. It is hypothesized that two notochords are formed but remain in too close proximity to develop separately, leading to conjoined twins.[
Another term that bears mention is diprosopus – defined as two faces with one head and one body.[
The authors believe that a focal defect causing a split notochord could best explain the abnormalities described in our patient. As the notochord induces brain development, the duplicate ventricular system, circulation and additional cerebral peduncle could be explained by a notochord split extending further caudally. Involvement of the cervical vertebrae suggests an extensive split occurring early in blastogenesis.
Spectrum of blastogenesis defects
Most cases of DPG are associated with hypothalamic thickening on MRI. This finding has alternately been interpreted as hypothalamic hamartoma or duplication of hypothalamic nuclei.[
The patient presented displays the most extensive collection of clinical features associated with DPG reported to date [
While bifid tongue is a commonly associated feature with DPG, most patients present with a common tongue base with a distal split. In the current case report, the split in tongues continues through the base. The two separate tongues are able to move volitionally and independently [
The only other feature that has been repeatedly associated with DPG is congenital diaphragmatic hernia (CDH) in 5/38 previous cases.[
Analysis of the patient's blood was performed by microarray-based comparative genomic hybridization which is designed to identify DNA copy number gains and losses. The probes are spaced every 35kb throughout the genome with one probe every 10kb in regions known to have clinical significance. Genomic imbalances less than 100kb may not be detected. This test does not detect point mutations, small deletions or duplications within genes. The result of analysis of 3,397 loci using olignucleotide probes did not detect any significant copy number abnormalities in the patient's DNA.
Genetic control of the notochord's influence on embryonic development is poorly understood in humans. Since microarray comparative genomic hybridization is a newer test, the majority of previously reported cases have not undergone such testing. While the current evidence supports an early notochordal split as explanation for the malformations observed in this patient, the cause of the split remains unknown. One possibility may be interference from the tumor causing mechanical obstruction leading to notochordal splitting around the mass, but it is difficult to determine if the teratoma was present at an early enough stage to influence development.
Duplication of the pituitary gland (DPG) appears to arise from blastogenesis defects. Splitting of the rostral end of the notochord can be used to explain the spectrum of malformations seen in these cases. The current report elucidates the broadest range of defects reported to date with the addition of a clival encephalocele, third cerebral peduncle, duplication of the odontoid process and double tongue. Considering the fact that DPG is uniquely present in the spectrum, we propose that these defects occur as part of a syndrome continuum that may be termed as DPG-plus syndrome.
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