Knockout mice with pituitary malformations help identify human cases of hypopituitarism.

BACKGROUND: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS). METHODS: The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations. RESULTS: Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features. CONCLUSIONS: The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.

Position statement on the diagnosis and management of congenital pituitary deficiency in adults: The French National Diagnosis and Treatment Protocol (NDTP).

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

Pituitary stalk interruption syndrome due to novel ROBO1 mutation presenting as combined pituitary hormone deficiency and central diabetes insipidus.

OBJECTIVES: The genetic causes of pituitary stalk interruption syndrome (PSIS) remain elusive in 95 % of cases. The roundabout receptor-1 gene (ROBO1) plays critical roles in axonal guidance and cell migration. Recently, mutations in the ROBO1 gene have been reported patients with PSIS. CASE PRESENTATION: We report a 2.9-year-old boy with PSIS who presented with combined pituitary hormone deficiency, central diabetes insipidus, and the classical triad of MRI findings. Through clinical exome sequencing using next-generation sequencing techniques, a previously unidentified novel heterozygous frame shift mutation in the ROBO1 gene was identified. This is the first report of ROBO1 mutation associated with posterior pituitary dysfunction. CONCLUSIONS: We conclude and emphasize that ROBO1 should be investigated in patients with PSIS. Our case is unique in the published literature in that we are first time reporting posterior pituitary dysfunction as manifestation of ROBO1 mutation. The full clinical spectrum of the mutations may not be fully known.

A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.

Biallelic pathogenic variants in the TTC26 gene are known to cause BRENS (biliary, renal, neurological, skeletal) syndrome, an ultra-rare autosomal recessive condition with only few patients published to date. BRENS syndrome is characterized by hexadactyly, severe neonatal cholestasis, and involvement of the brain, heart, and kidney, however the full phenotypic and genotypic spectrum is unknown. Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006-5 T > C) in a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect. Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate. The variant is considered to affect correct splicing by the loss of the canonical acceptor splice site and activation of a cryptic acceptor splice site. Hereby, our patient represents one additional patient with BRENS syndrome carrying a previously unreported TTC26 variant. Furthermore, we confirm the involvement of the pituitary gland to be a common clinical feature of the syndrome and broaden the clinical spectrum of TTC26 ciliopathy to include facial clefts and a probable hearing involvement.

Obesity, Overweight, and Pituitary Stalk Interruption Syndrome in Children and Young Adults.

CONTEXT: Pituitary stalk interruption syndrome (PSIS) is rare in the pediatric population. It combines ectopic posterior pituitary stalk interruption and anterior pituitary hypoplasia with hormonal deficiencies. The phenotype is highly heterogeneous and obesity/overweight seems to be underreported in the literature. OBJECTIVE: To identify patients with PSIS and obesity or overweight, describe their phenotype, and compare them with patients with PSIS without overweight/obesity. METHODS: Sixty-nine children and young adults with PSIS in a Toulouse cohort from 1984 to 2019 were studied. We identified 25 obese or overweight patients (OB-OW group), and 44 were nonobese/overweight (NO group). Then the groups were compared. RESULTS: All cases were sporadic. The sex ratio was 1.6. The main reason for consultation in both groups was growth retardation (61% in OB-OW group, 77% in NO group). History of neonatal hypoglycemia was more common in the OB-OW than in the NO group (57% vs 14%, P = .0008), along with extrapituitary malformations (64% vs 20%, P < 0001). The incidence of caesarean section was higher in the OB-OW group (52%) than in the NO group (23%), although not significant (P = .07). CONCLUSION: Patients with PSIS who are obese/overweight display interesting phenotypic differences that suggest hypothalamic defects. Studies are needed that include additional information on hormonal levels, particularly regarding oxytocin and ghrelin.

A homozygous Y443C variant in the RNPC3 is associated with severe syndromic congenital hypopituitarism and diffuse brain atrophy.

Biallelic RNPC3 variants have been reported in a few patients with growth hormone deficiency, either in isolation or in association with central hypothyroidism, congenital cataract, neuropathy, developmental delay/intellectual disability, hypogonadism, and pituitary hypoplasia. To describe a new patient with syndromic congenital hypopituitarism and diffuse brain atrophy due to RNPC3 mutations and to compare her clinical and molecular characteristics and pituitary functions with previously published patients. A 20-year-old female presented with severe growth, neuromotor, and developmental delay. Her weight, height, and head circumference were 5135 gr (-25.81 SDS), 68 cm (-16.17 SDS), and 34 cm (-17.03 SDS), respectively. She was prepubertal, and had dysmorphic facies, contractures, and spasticity in the extremities, and severe truncal hypotonia. There were no radiological signs of a skeletal dysplasia. The bone age was extremely delayed at 2 years. Investigation of pituitary function revealed growth hormone, prolactin, and thyroid-stimulating hormone deficiencies. Whole-exome sequencing revealed a novel homozygous missense (c.1328A > G; Y443C) variant in RNPC3. Cranial MRI revealed a hypoplastic anterior pituitary with diffuse cerebral and cerebellar atrophy. The Y443C variant in RNPC3 associated with syndromic congenital hypopituitarism and abnormal brain development. This report extends the RNPC3-related hypopituitarism phenotype with a severe neurodegenerative presentation.

Persisting embryonal infundibular recess (PEIR) and transsphenoidal-transsellar encephaloceles: distinct entities or constituents of one continuum?

Persisting embryonal infundibular recess (PEIR) is a very rare anomaly of the floor of the third ventricle in which the embryonic morphology of the infundibular recess (IR) persists. The exact underlying mechanism of development of PEIR is unknown, and the anomaly has been reported as an isolated finding or in association with other conditions. On the other hand, trans-sphenoidal encephaloceles are the rarest form of basal encephaloceles. The trans-sphenoidal trans-sellar encephalocele (TSE) is the least common variant in which the pituitary gland, pituitary stalk, optic pathways, parts of the third ventricle and IR may be present within the encephalocele. We recently treated one patient with TSE. Based on the observed morphological similarity of the IR in our patient and in the published cases of PEIR, we reviewed the literature in order to validate the hypothesis that PEIR and TSE may possibly belong to one spectrum of malformations. Across the published reports, the morphology of the IR in TSE is very closely similar to PEIR. Moreover, radiological, patho-anatomical, and embryological evidence is in support to our hypothesis that PEIR and TSE are most likely the two extremes of the same continuum of malformations.

Presenting symptoms and endocrine dysfunction in Rathke cleft cysts - a two-centre experience.

INTRODUCTION: Rathke cleft cysts (RCC) arise as developmental abnormalities of the pituitary gland and are usually diagnosed incidentally. However, they may present with headaches, visual impairment, or pituitary dysfunction. Rathke cleft cysts are poorly described in the Polish literature. We aimed to characterize presenting symptoms, associated endocrine dysfunction, and concomitant disorders in the Polish population of patients with RCC. MATERIAL AND METHODS: We performed a retrospective analysis of medical records of 102 patients diagnosed with RCC between 2006 and 2021 at Heliodor Swiecicki Clinical Hospital in Poznan and Independent Public Clinical Hospital No. 4 in Lublin. RESULTS: The cohort was 72% female, with a mean age of 43 years. The median maximal cyst diameter was 7 mm. The majority of subjects were overweight or obese and presented lipid profile or glucose disturbances. Common presenting symptoms included headache, vertigo, and visual impairment. Less frequently we observed sexual dysfunction, irregular menses, galactorrhoea, or fatigue. Hormonal abnormalities were identified in 30% of patients, with hyperprolactinaemia being the commonest endocrinopathy (23%). Pituitary function in patients with RCC did not correlate with cyst size. Both concomitant pituitary adenomas and pineal cysts were diagnosed in 3% of patients. A considerable proportion of subjects were diagnosed with Hashimoto's thyroiditis and multinodular goitre. CONCLUSIONS: RCCs occur mostly in females and may result in a variety of symptoms and hormonal dysfunction. Patients require a full clinical and endocrine evaluation regardless of the cyst diameter. We report a substantial co-occurrence of RCC and metabolic disorders and primary thyroid diseases, which requires further investigation.

Clinical features, radiological profiles, pathological features and surgical outcomes of pituicytomas: a report of 11 cases and a pooled analysis of individual patient data.

BACKGROUND: Pituicytoma is an extremely rare low-grade glial tumor that is closely related to the neurohypophysis axis. Most studies of pituicytomas include only several cases. To better understand this disease, we reviewed a series of cases of pituicytomas. The diagnosis and treatment of pituicytoma must be further elucidated. METHODS: Eleven patients with pituicytoma admitted to Beijing Tiantan Hospital from 2012 to 2019 were selected. The clinical features, including radiological and histological examination, surgical records and prognosis were reviewed. Sixty-eight other previously published cases of pituicytoma also were used to analyze the predictive factors for the results. The Cox regression model was used for univariate and multivariate analyses. RESULTS: Our patients included 5 males (45.5%) and 6 females (54.5%), with a mean age of 49.3 years. The tumor was located in the suprasellar region in 5 patients (45.5%), intrasellar region in 4 patients (36.4%), and intrasellar-suprasellar region in 2 patients (18.2%). All patients were misdiagnosed with other common tumors in the sellar region before the operation. During the operation, gross total resection (GTR) of the tumor was achieved in 6 patients (54.5%), and subtotal resection (STR) was achieved in 5 patients (45.5%). The mean progression-free survival (PFS) time was 29.82 months. Tumor progression after surgical resection occurred in 4 patients (36.4%). Among them, 60.0% of the patients (cases 4, 5, 7) with STR experienced progression, while 16.7% of the patients (case 2) with GTR experienced progression. Combined with the 68 cases in the literature, GTR was an independent risk factor for PFS time (P < 0.05). CONCLUSIONS: Pituicytomas are more common in middle-aged people and the sellar region. The clinical manifestations of pituicytomas are different, but no diagnostic clinical features have been identified other than an abnormally abundant blood supply. Currently, GTR is the best approach for the treatment of pituicytomas. More patients and longer follow-up periods were needed to further elucidate the biological features of pituicytomas.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature.

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.

Co-Occurrence of Pineal-Region and Pituitary-Stalk Hemangioblastomas in a Patient Presenting with Von Hippel-Lindau Disease ­ A Case Report

Introduction Hemangioblastomas of the pineal region or pituitary stalk are extremely rare. Only two cases of hemangioblastomas involving the pineal region have been reported, and four involving the pituitary stalk. The purpose of the present manuscript is to describe an unusual case of supposed hemangioblastoma found concomitantly in the pineal region and pituitary stalk of a patient diagnosed with Von Hippel-Lindau (VHL) disease. Case Report A 35-year-old female patient with a previous diagnosis of VHL complaining of occipital headaches and balance disturbances for three weeks, who previously had a cerebellar hemangioblastoma resected. The visual characteristics of the tumor suggested a friable vascular lesion with a reddish-brown surface, and an incisional biopsy was performed. The tumor consisted of a dense vascular network surrounded by fibrous stroma abundant in reticulin and composed by both fusiform and dispersed xanthomatous cells; the immunohistochemistry was immunopositive for neuronspecific enolase and immunonegative for epithelial membranous antigen. The patient has been monitored closely for 2 years, and the supratentorial masses have not presented any volume alteration. Conclusion This rare association must be taken into account in patients with VHL disease, or at least be suspected in patients who present a thickening of the pituitary stalk and a pineal-region mass. We believe a biopsy of our asymptomatic patient could have been dangerous due to inherent complications like intraoperative bleeding. We recommend close observation of asymptomatic lesions with MRIs every six months or until the lesions become symptomatic. If the pineal-region tumor does become symptomatic, gross resection via a transcallosal approach would be ideal.

Dysgenesis and Dysfunction of the Pancreas and Pituitary Due to FOXA2 Gene Defects.

CONTEXT: Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extrapituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut, and pancreatic development. OBJECTIVE: This work aims to characterize 2 patients with syndromic hypopituitarism due to FOXA2 gene defects. RESULTS: We report a novel heterozygous nonsense c.616C > T(p.Q206X) variant that leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the glucose transporter type 2 (GLUT2)-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 Mb deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. CONCLUSION: Our 2 cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.

Biochemical predictors of structural hypothalamus-pituitary abnormalities detected by magnetic resonance imaging in men with secondary hypogonadism.

PURPOSE: Organic conditions underlying secondary hypogonadism (SH) may be ascertained by magnetic resonance imaging (MRI) of the hypothalamic-pituitary region that could not be systematically proposed to each patient. Based upon limited evidence, the Endocrine Society (ES) guidelines suggest total testosterone (T) < 5.2 nmol/L to identify patients eligible for MRI. The study aims to identify markers and their best threshold value predicting pathological MRI findings in men with SH. METHODS: A consecutive series of 609 men seeking medical care for sexual dysfunction and with SH (total T < 10.5 nmol/L and LH ≤ 9.4 U/L) was retrospectively evaluated. An independent cohort of 50 men with SH was used as validation sample. 126 men in the exploratory sample and the whole validation sample underwent MRI. RESULTS: In the exploratory sample, patients with pathological MRI findings (n = 46) had significantly lower total T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate specific antigen (PSA) than men with normal MRI (n = 80). Receiver Operating Characteristics analysis showed that total T, LH, FSH and PSA are accurate in identifying men with pathologic MRI (accuracy: 0.62-0.68, all p < 0.05). The Youden index was used to detect the value with the best performance, corresponding to total T 6.1 nmol/L, LH 1.9 U/L, FSH 4.2 U/L and PSA 0.58 ng/mL. In the validation cohort, only total T ≤ 6.1 nmol/L and LH ≤ 1.9 U/L were confirmed as significant predictors of pathologic MRI. CONCLUSION: In men with SH, total T ≤ 6.1 nmol/L or LH ≤ 1.9 U/L should arise the suspect of hypothalamus/pituitary structural abnormalities, deserving MRI evaluation.

Pituitary hypoplasia is the best MRI predictor of the severity and type of growth hormone deficiency in children with congenital growth hormone deficiency.

OBJECTIVES: Congenital idiopathic growth hormone deficiency (GHD) is associated with various MRI abnormalities, including sellar and extrasellar abnormalities. However, it remains contentious whether MRI brain findings could provide an additional avenue for precisely predicting the differentiation of GHD based on severity and type {isolated GHD or multiple pituitary hormone deficiencies (MPHD)}. This study aimed to ascertain the abnormality that is the best predictor of severity and type of GHD amongst the different MRI findings. METHODS: We conducted an analytical cross-sectional study, including 100 subjects diagnosed with idiopathic GHD. Patients were grouped into severe GHD, partial GHD, and MPHD and into groups based on the presence of pituitary hypoplasia, extrasellar brain abnormalities (EBA), and presence of ectopic posterior pituitary or pituitary stalk abnormalities (EPP/PSA) or both. RESULTS: Sixty six percentage of subjects had isolated GHD, 34% had MPHD, 71% had severe GHD, and 29% had partial GHD. Pituitary hypoplasia was the most common finding, observed in 53% of patients, while 23% had EBA, and 25% had EPP/PSA. Pituitary hypoplasia was observed to be the best predictor of severity of GHD with an odds ratio (OR) of 10.8, followed by EPP/PSA (OR=2.8), and EBA was the weakest predictor (OR=1.8). Pituitary hypoplasia was the only finding to predict MPHD (OR=9.2) significantly. On ROC analysis, a Pituitary height SDS of -2.03 had the best detection threshold for both severe GHD and MPHD. CONCLUSIONS: We observed Pituitary hypoplasia to be not only the most frequent MRI abnormality but also the best predictor of severe GHD and MPHD amongst various sellar and extrasellar abnormalities.

A mouse model of BBS identifies developmental and homeostatic effects of BBS5 mutation and identifies novel pituitary abnormalities.

Primary cilia are critical sensory and signaling compartments present on most mammalian cell types. These specialized structures require a unique signaling protein composition relative to the rest of the cell to carry out their functions. Defects in ciliary structure and signaling result in a broad group of disorders collectively known as ciliopathies. One ciliopathy, Bardet-Biedl syndrome (BBS; OMIM 209900), presents with diverse clinical features, many of which are attributed to defects in ciliary signaling during both embryonic development and postnatal life. For example, patients exhibit obesity, polydactyly, hypogonadism, developmental delay and skeletal abnormalities along with sensory and cognitive deficits, but for many of these phenotypes it is uncertain, which are developmental in origin. A subset of BBS proteins assembles into the core BBSome complex, which is responsible for mediating transport of membrane proteins into and out of the cilium, establishing it as a sensory and signaling hub. Here, we describe two new mouse models for BBS resulting from a targeted LacZ gene trap allele (Bbs5-/-) that is a predicted congenital null mutation and conditional (Bbs5flox/flox) allele of Bbs5. Bbs5-/- mice develop a complex phenotype consisting of increased pre-weaning lethality craniofacial and skeletal defects, ventriculomegaly, infertility and pituitary anomalies. Utilizing the conditional allele, we show that the male fertility defects, ventriculomegaly and pituitary abnormalities are only present when Bbs5 is disrupted prior to postnatal day 7, indicating a developmental origin. In contrast, mutation of Bbs5 results in obesity, independent of the age of Bbs5 loss.

Pituitary stalk interruption syndrome: A rare case report and literature review.

RATIONALE: Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. It is characterized by the triad of thin or interrupted pituitary stalk, absent or ectopic posterior lobe, and hypoplastic or aplastic anterior lobe. Moreover, this condition is considered rare. PATIENT CONCERNS: A 23-year-old male patient presented with a history of short stature and hypogonadism. Laboratory assessment revealed low thyroxine, cortisol, and adrenocorticotropic hormone levels, which are consistent with adrenal insufficiency without hypoglycemia. The insulin-induced hypoglycemia tolerance test finding indicated growth hormone (GH) deficiency. Moreover, magnetic resonance imaging revealed an interrupted pituitary stalk, ectopic posterior pituitary, and hypoplastic anterior pituitary. This triad of symptoms was indicative of PSIS. DIAGNOSIS: INTERVENTIONS:: The patient was deficient in adrenaline, thyroxine, gonadal steroid, and GH. Thus, glucocorticoid replacement therapy was initiated, followed by euthyrox, androgen, and human chorionic gonadotropin treatment. Calcium tablets, calcitriol, and alendronate sodium were used for the management of osteoporosis. The patient was 164 cm tall, and his bone age was approximately 15 years old. However, owing to a poor economic condition, the family did not proceed with GH therapy. OUTCOMES: The patient did not present with adrenal or hypothyroidism crisis after receiving poly-hormonal replacement therapy. His secondary sexual characteristics began to develop. However, owing to a short treatment window period, the patient could not receive the required treatment. Hence, whether the patient would have a normal fertility function needs to be confirmed. LESSONS: PSIS is a rare disease with various clinical characteristics. During the neonatal period and infancy, the signs and symptoms of PSIS are often not evident. Therefore, diagnosis is delayed. The early detection of hormone deficiency and treatment initiation can affect both the quality of life and the prognosis of patients with PSIS. Thus, the diagnosis and treatment of this disease must be improved to help patients achieve a better quality of life and to prevent reproductive health problems.

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.

Ciliopathies are a heterogeneous group of disorders, related to abnormal ciliary function. Severe biliary ciliopathy, caused by bi-allelic mutations in TTC26, has been recently described in the context of a syndrome of polydactyly and severe neonatal cholestasis, with brain, kidney and heart involvement. Pituitary involvement has not been previously reported for patients with this condition. Pituitary stalk interruption syndrome (PSIS) is a congenital anomaly of the pituitary gland, diagnosed by characteristic MRI findings. We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26 in pituitary development.

Duplication of the pituitary gland and basilar artery, with multiple midline fusion defects and craniofacial anomalies.

Duplication of the pituitary gland (DPG) is a phenomenon with no clear syndromic association. This case adds to the literature as a DPG-plus syndrome patient with multiple fusion defects of unknown etiology, fetal risk factors of first trimester tobacco usage and intrauterine drug exposure. An 8-month old female presented with noisy breathing, poor feeding, cleft palate, seizures and failure to thrive. MRI scan revealed duplicate pituitary gland, tubomammillary fusion, absent cleavage of brainstem and superior cerebellar peduncles, and cervical spinal malformations. We performed an airway evaluation, with a glossomandibulopexy for glossoptosis, and a primary palate repair.

Unique near-complete deletion of GLI2 in a patient with combined pituitary hormone deficiency and post-axial polydactyly.

INTRODUCTION: Combined pituitary hormone deficiency (CPHD) can cause a broad spectrum of health problems, ranging from short stature only, to convulsions or even death. In the majority of patients, the cause is unknown. METHODS: The idex case had unexplained CPHD, pituitary anomalies on MRI and polydactyly. In the patients and her unaffected parents, we performed SNP array analysis and Whole Exome Sequencing, after candidate gene analysis turned out negative. RESULTS: We found a unique de novo heterozygous 229.9 kb deletion in the index case on chr. 2q14.2. This deletion covered 12 out of the 13 coding exons of the GLI2 gene, a transcription factor involved in midline formation and previously associated with CPHD. As reported GLI2 deletions and mutations show a large phenotypic variability, we performed a genotype-phenotype analysis. This revealed that GLI2 missense mutations usually present with a 'ppp-only' phenotype (pituitary anomalies ± postaxial polydactyly without brain phenotype), whereas the 'ppp-plus' phenotype (with major brain malformations and/or intellectual disabilities) is more frequent in patients with larger deletions, and those with frameshift mutations/point mutations or splice variants resulting in a stop codon (p < .001). CONCLUSION: The present case shows that a deletion of the GLI2 gene only (not affecting any of the adjacent genes) causes pituitary anomalies without brain phenotype. This suggests that brain phenotype only occurs when additional genes adjacent to GLI2 are deleted, or when mutations result in truncated GLI2 mRNA/protein. However, due to the lack of functional data for many GLI2 mutations and based on the available information regarding variable penetrance, phenotype-genotype correlations need to be made with caution.

Growth and Adult Height during Human Growth Hormone Treatment in Chinese Children with Multiple Pituitary Hormone Deficiency Caused by Pituitary Stalk Interruption Syndrome: A Single Centre Study

Objective: The aim was to assess growth velocity (GV) during human recombinant growth hormone (hGH) treatment of children with multiple pituitary hormone deficiency (MPHD) caused by pituitary stalk interruption syndrome (PSIS) and to analyze the characteristics of patients that attained normal adult heights. Methods: Data from 74 (16 female) children with MPHD caused by PSIS with GH, thyroid stimulating hormone, gonadotropin and adrenocorticotropic hormone deficiencies were collected. Subjects were divided into groups: 12 pre-pubescent females (Female-Group) and 36 pre-pubescent males (Male-Group 1). The remaining 22 males were further sub-divided into two groups (Male-Group 2 and Male-Group 3) according to the initiation of gonadotropin replacement treatment, based on bone age and height. Results: No differences in change in height standard deviation score (△HtSDS) and GV were observed at different time points of hGH treatment between the Female-Group and Male-Group 1 (p>0.05). GV was significantly greater in the first year of hGH therapy than in subsequent years: Female-Group p=0.011; Male-Group 1 p<0.001; Male-Group 2 p=0.005; and Male-Group 3 p=0.046. Adult height was achieved by 23 (19 males and 4 females) patients. The total gain in height positively correlated with the GV during the first year (r=0.626, p<0.001). Conclusion: GV during hGH treatment were similar amongst pre-pubescent males and females with MPHD caused by PSIS. GV during the first year of hGH treatment appears to be an effective predictor of final height in patients with MPHD caused by PSIS.