Duplication of the pituitary gland (DPG)-plus syndrome is an extremely rare developmental malformation of unknown aetiology. Two unreported patients of DPG-plus syndrome are described. Underlying genetic defects were explored, including chromosomal microarray (CMA), whole exome sequencing (WES) and mRNA analysis. A literature review was presented. Patient 1 had DPG, palatal cleft, bifid tongue, intraoral teratoma, lingual hamartoma and duplicated basilar artery and odontoid process. Patient 2 had DPG, epignathus teratoma, a nasal mass, choanal atresia, cleft palate, bifid tongue, abnormal basilar artery and fused upper cervical spine. CMA yielded normal results. WES of patient 1 disclosed a novel splice site PTCH2 variant, c.1590+1G>A, leading to exon 12 skipping and an in-frame deletion of 44 amino acids. WES of patient 2 revealed no candidate variants. A literature review of 51 cases showed mostly reported in childhood and female sex (80%). The leading anomalies identified included DPG (100%), cleft palate (68.6%), anomalous cervical spine (56.9%), hypothalamic mass/enlargement (58.8%), intraoral teratoma (58.8%), basilar arterial abnormalities (43.1%) and bifid/trifid tongue (23.5%). Non-craniofacial anomalies were found in <10% of cases. Late complications included precocious puberty, all in female patients, and hypogonadotropic hypogonadism in a few patients. Two new cases of DPG-plus syndrome were reported, with rare findings of epignathus and choanal atresia. We propose that DPG-plus syndrome may result from a double hit in one of the genes involved in SHH signalling, arising from a germline pathogenic variant with mosaicism for a somatic pathogenic variant or digenic/oligogenic inheritance of the SHH signalling-related genes.

Duplication of the pituitary gland is a rare anomaly with variable associated craniofacial malformations (duplicated pituitary gland plus syndrome). Thus far, malformations have only been reported in the craniofacial structures, central nervous system (CNS), and spine. This report illustrates a severe case with additional, previously unreported body features including anomalies of the lungs, heart, liver, spleen, and abdominal vasculature. A description of this case will aid in comprehensive diagnosis of anomalies in patients with duplicated pituitary gland plus syndrome. Moreover, this case may improve understanding of the etiology of this rare disorder and its embryological underpinnings.

Duplication of the pituitary gland is a rare developmental anomaly. Multiple associated craniofacial malformations have previously been reported with the largest series to date consisting of 5 patients. In this multi-institutional series of 10 patients, we present a detailed review of the imaging features and discuss a possible overarching pathogenesis that would explain most of the detected malformations. Inclusion criteria for this retrospective imaging review were the presence of a pituitary stalk and gland duplication and the characteristic appearance of the hypothalamic ventral midline. In addition to the clinical presentation, we recorded the imaging findings of 10 patients (9 girls) through onsite and online reviews. Genetic analysis was available for 6 patients. The duplicated pituitary stalk and gland showed normal imaging appearances in all patients. Mammillary bodies were clearly identified lateral to the characteristic prominence of the hypothalamic ventral midline. Strands of tissue extending to the anterior dura ("limited ventral myeloschisis") were noted at the medulla oblongata in 10, and at the cervical spinal cord in 7 patients. The medulla oblongata showed a "butterfly" appearance on axial images in 9 patients. Ten patients had cervical segmentation anomalies ("zipperlike"), 9 had anterior-posterior brainstem patterning defects (small pons, elongated medulla), and corpus callosum measurements were abnormal in all patients. Three patients each presented with diencephalic-mesencephalic junction abnormalities and 4 with an anterior mesencephalic "cap." An oropharyngeal teratoma was present in 4 patients. Genetics was normal in 3 of the 6 patients studied; the remainder were found to have mutations in EFNB1 and a gene variant of GIT1, 2 copies of 7 and 8 exon of SMN1 gene, and 2.126 megabase duplication at bands q11.1 and q11.2 of 1 chromosome 15, respectively. Duplication of the pituitary gland presents as well-defined craniofacial and cervical spine malformation phenotype. Axial mesoderm duplication generating an excess of Sonic Hedgehog may be the primary embryologic driver leading to this condition.

The prenatal diagnosis of epignathus presents a unique challenge for physicians. Differential diagnosis is usually based on the anatomic location of the tumor. Typical prenatal ultrasound characteristics of epignathus include a mixed solid and cystic lesion with vascularity in the solid component, originating from the hard or soft palate, and it is often associated with other anomalies such as craniofacial clefts or trans-sphenoidal intracranial extension. Herein, we present a case of prenatal diagnosis of epignathus with rare ultrasonographic findings, prenatal management requiring collaborative efforts of a multidisciplinary team, and a well-planned innovative ex utero intrapartum treatment procedure. In addition, this report highlights the evolving postnatal diagnosis of the rare developmental anomaly, duplication of the pituitary gland-plus syndrome, which includes various midline craniofacial, central nervous system, spinal, and endocrine abnormalities.

Duplication of the pituitary gland (DPG) is an extremely rare malformation. DPG is associated with a wide variety of midline and central nervous system malformations (DPG-plus syndrome). We present the computed tomography (CT), magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) findings of a rare case of DPG with associated tuberomammillary fusion resulting in a hypothalamic mass-like configuration, oropharyngeal teratoma, cleft palate, hypertelorism, duplicated/broad sella, duplication/low bifurcation of the basilar artery, and craniovertebral midline anomalies. Qualitative interpretation of DTI yielded normal white matter organization of the brain. The duplication of the prechordal plate and the rostral end of the notochordal plate/notochord is thought to be the main factor leading to a duplication of the pituitary primordium and resulting in the formation of two morphologically normal glands. The time of induction of the teratogenic influence, the extent of the prechordal plate and notochordal plate/notochord abnormalities, and the faulty interactions are believed to be the reason for the wide spectrum of associated midline abnormalities.