Pituitary Hypoplasia Research Articles

Pituitary Stalk Interruption Syndrome: Baseline Characteristics and Long-Term Evolution of Two Pediatric Cases with Rare Presentation

Background and Aims
 Pituitary stalk interruption syndrome (PSIS) is characterized by the presence of a thin or absent pituitary stalk in association with a hypoplastic or aplastic anterior pituitary or an ectopic neurohypophysis [1,2]. The phenotype associated with PSIS has a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects [1]. The aim of our study is to illustrate the heterogeneity of PSIS through a complete description of the clinical, biological and imagistic differences between our cases.
 Case Reports
 We describe two rare pediatric cases. The first case was a 6-year-old boy admitted to our department with polyuro-polydipsic syndrome and underdeveloped external genitals. He had a history of neonatal micropenia and a family medical history of panhypopituitarism and midline malformations. Physical examination revealed normal stature (height: 117 cm, −0.4 SDS), obesity (BMI: 25.2 Kg/mp, over 97th percentile), micropenia (stretched penile length: 3 cm) and non-palpable testes. Initially, his urine output was 5000 mL/24 h, with a low urine specific gravity of 1005–1010, and no increase after water deprivation test, with an appropriate response after desmopresin administration. He presented normoglycemia. Serum gonadotropin (FSH, LH) and testosterone levels were low, with no response after GnRH-analogue stimulation test. IGF-1 levels were low-normal. His Copeptin value was decreased. Pituitary MRI showed anterior pituitary hypoplasia, absence of the pituitary stalk and neurohypophysis.
 The second case was a 4-year-old girl referred to our service for growth retardation. She had a history of neonatal prolonged jaundice and intermittent seizures, for which she was prescribed phenobarbital for 2 years. Her physical examination described short stature (height: 90.5 cm, −3.3 SD), underweight (BMI: 15.87 Kg/m2, 15–25th percentile), head dysmorphic features: medial epicanthal fold, depressed nasal bridge, anteverted nares, ogival palate. She had a bone age of 2 years. The initial evaluation diagnosed severe GH deficiency, and during the next 3 years of follow-up she developed ACTH, TSH and FSH-LH deficiencies. MRI examination indicated anterior pituitary hypoplasia, absence of pituitary stalk and ectopic neurohypophysis.
 Discussion
 Central diabetes insipidus is rarely reported in patients with PSIS (0–4%) [1,3]. Although GH deficiency was found almost ubiquitous in PSIS, our first patient had no growth retardation. Normal linear growth despite abnormal GH secretion was also reported [4]. Neonatal cholestasis was linked to ACTH deficiency, which can also be a cause of recurrent hyponatremia [1]. There were no signs of ACTH deficiency or hyponatremia in our second patient in the neonatal period. Few reports showed cases of PSIS that were diagnosed with acute epileptic seizures accompanied by hyponatremia [5]. The rapidly progressive evolution to combined pituitary deficiency observed in PSIS cases [4] with neonatal features was also recognized in our patients.
 Conclusions
 The phenotype associated with PSIS can be highly heterogeneous. It is important to increase the awareness of PSIS, especially in the neonatal period when the features of PSIS can be easily overlooked. We also emphasize the importance of patient follow-up as an essential part of an adequate management.

Loss-of-function variants in TBC1D32 underlie syndromic hypopituitarism

To read the full abstract: J Clin Endocrinol Metab. 2020 Feb 15. pii: dgaa078. doi: 10.1210/clinem/dgaa078. PMID: 32060556.

Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells

Pituitary develops from oral ectoderm in contact with adjacent ventral hypothalamus. Impairment in this process results in congenital pituitary hypoplasia (CPH); however, there have been no human disease models for CPH thus far, prohibiting the elucidation of the underlying mechanisms. In this study, we established a disease model of CPH using patient-derived induced pluripotent stem cells (iPSCs) and 3D organoid technique, in which oral ectoderm and hypothalamus develop simultaneously. Interestingly, patient iPSCs with a heterozygous mutation in the orthodenticle homeobox 2 (OTX2) gene showed increased apoptosis in the pituitary progenitor cells, and the differentiation into pituitary hormone-producing cells was severely impaired. As an underlying mechanism, OTX2 in hypothalamus, not in oral ectoderm, was essential for progenitor cell maintenance by regulating LHX3 expression in oral ectoderm via FGF10 expression in the hypothalamus. Convincingly, the phenotype was reversed by the correction of the mutation, and the haploinsufficiency of OTX2 in control iPSCs revealed a similar phenotype, demonstrating that this mutation was responsible. Thus, we established an iPSC-based congenital pituitary disease model, which recapitulated interaction between hypothalamus and oral ectoderm and demonstrated the essential role of hypothalamic OTX2.

Genetic spectrum and predictors of mutations in four known genes in Asian Indian patients with growth hormone deficiency and orthotopic posterior pituitary: an emphasis on regional genetic diversity.

Regional variation in prevalence of genetic mutations in growth hormone deficiency (GHD) is known. Study phenotype and prevalence of mutations in GH1, GHRHR, POU1F1, PROP1 genes in GHD cohort. One hundred and two patients {Isolated GHD (IGHD): 79; combined pituitary hormone deficiency (CPHD): 23} with orthotopic posterior pituitary were included. Auxologic, hormonal and radiological details were studied. All four genes were analysed in IGHD patients. POU1F1 and PROP1 were studied in CPHD patients. Of 102, 19.6% were familial cases. Height SDS, mean (SD) was - 5.14 (1.63). Peak GH, median (range) was 0.47ng/ml (0-6.59), 72.5% patients had anterior pituitary hypoplasia (APH). Twenty mutations (novel: 11) were found in 43.1% patients (n = 44, IGHD-36, CPHD-8). GHRHR mutations (n = 32, p.Glu72* = 24) were more common than GH1 mutations (n = 4) in IGHD cohort. POU1F1 mutations (n = 6) were more common than PROP1 mutations (n = 2) in CPHD cohort. With few exceptions, this prevalence pattern is contrary to most studies in world-literature. No patients with peak GH > 4ng/ml had mutations, signifying it as negative predictor. While many parameters were significant on univariate analysis, only positive family history and lower median peak GH levels were significant predictors of mutations on multivariate analysis in IGHD patients. At variance with world literature, we found reverse predominance of GHRHR over GH1 mutations, POU1F1 over PROP1 mutations and predominance of GHRHR p.Glu72* mutations thus re-affirming the regional diversity in GHD genetics. We report positive and negative predictors of mutations in GHD.

Long-term postnatal outcome of fetuses with prenatally suspected septo-optic dysplasia.

ABSTRACTObjectivesSepto‐optic dysplasia (SOD) is a clinical syndrome characterized by varying combinations of optic nerve hypoplasia, pituitary gland hypoplasia and abnormal cavum septi pellucidi. It is suspected on prenatal imaging when there is non‐visualization or hypoplasia of the septal leaflets. Long‐term postnatal outcomes of fetuses with prenatally suspected SOD have been documented poorly. The aims of this study were to describe the natural history of deficient septal leaflets, to quantify the incidence of postnatally confirmed SOD and to document the visual, endocrine and long‐term neurodevelopmental outcomes of these infants.MethodsThis was an observational retrospective study of all fetuses with prenatal imaging showing isolated septal agenesis, assessed at a single tertiary center over an 11‐year period. Pregnancy, delivery and neonatal outcomes and pre‐ and postnatal imaging findings were reviewed. Neonatal evaluations or fetal autopsy reports were assessed for confirmation of SOD. Ophthalmologic, endocrine, genetic and long‐term developmental evaluations were assessed. Imaging findings and outcome were compared between infants with and those without postnatally confirmed SOD.ResultsOf 214 fetuses presenting with septal absence on prenatal ultrasound and magnetic resonance imaging (MRI), 18 (8.4%) were classified as having suspected isolated septal agenesis suspicious for SOD. Uniform prenatal MRI findings in cases with suspected SOD included remnants of the leaflets of the cavum septi pellucidi, fused forniceal columns, normal olfactory bulbs and tracts and a normal optic chiasm. Twelve fetuses were liveborn and five (27.8%) had postnatally confirmed SOD. Only two of these five fetuses had additional prenatal imaging features (pituitary cyst, microphthalmia and optic nerve hypoplasia) supporting a diagnosis of SOD. The other three confirmed SOD cases had no predictive prenatal or postnatal imaging findings that reliably differentiated them from cases without confirmed SOD. Visual and endocrine impairments were present in two (40%) and four (80%) cases with confirmed SOD, respectively. In those with visual and/or endocrine impairment, developmental delay (median age at follow‐up, 2.5 (interquartile range, 2.5–7.0) years) was common (80%) and mostly severe. Neonates with isolated septal agenesis and a lack of visual or endocrine abnormalities to confirm SOD had normal development.ConclusionsOnly a quarter of fetuses with isolated septal agenesis suggestive of SOD will have postnatal confirmation of the diagnosis. Clinical manifestations of SOD are variable, but neurodevelopmental delay may be more prevalent than thought formerly. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

MITOL dysfunction causes dwarfism with anterior pituitary hypoplasia

In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.

PTPσ Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses

SummaryLeukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic organizers. The synaptic role of vertebrate LAR-RPTPs in vivo, however, remains unclear. In the current study, we analyzed the synaptic role of PTPσ using newly generated, single conditional knockout (cKO) mice targeting PTPσ. We found that the number of synapses was reduced in PTPσ cKO cultured neurons in association with impaired excitatory synaptic transmission, abnormal vesicle localization, and abnormal synaptic ultrastructure. Strikingly, loss of presynaptic PTPσ reduced neurotransmitter release prominently at excitatory synapses, concomitant with drastic reductions in excitatory innervations onto postsynaptic target areas in vivo. Furthermore, loss of presynaptic PTPσ in hippocampal CA1 pyramidal neurons had no impact on postsynaptic glutamate receptor responses in subicular pyramidal neurons. Postsynaptic PTPσ deletion had no effect on excitatory synaptic strength. Taken together, these results demonstrate that PTPσ is a bona fide presynaptic adhesion molecule that controls neurotransmitter release and excitatory inputs.

MON-234 síNdrome de InterrupcióN del Tallo Pituitario Que Se Presenta Como Amenorrea Primaria

Pituitary stalk interruption syndrome presenting as primary amenorrhea.The pituitary stalk interruption syndrome is a rare congenital defect that is characterized by the absence or thinning of the pituitary stalk, an absent or ectopic posterior pituitary lobe, and hypoplasia or aplasia of the anterior lobe. The clinical presentation is variable.It is usually diagnosed in the neonatal period due to the clinical manifestations that arise as a consequence of hormonal deficiencies. However some patients are diagnosed at a latter stage in life. Growth hormone deficiency it is observed in virtually all patients and can be associated to other anterior pituitary hormonal deficiencies. There is a high frequency of associated extra-pituitary malformations including those involving the central nervous system and the craniofacial structures.We report the case of a 19-year-old woman with primary amenorrhea, lack of secondary sexual characteristics, short stature, low body mass index due to hypergonadotropic hypogonadism and growth hormone deficiency. The remaining pituitary hormones were normal. A pelvic ultrasound revealed orthotopic ovaries and uterus that were decreased in size. Her karyotype was normal. An MRI of the sellar region revealed an ectopic posterior pituitary lobe, and anterior pituitary hypoplasia with a thin pituitary stalk. The patient was treated with estradiol valerate and norgestrel as well as with growth hormone.In conclusion, the pituitary stalk interruption syndrome is a rare form of congenital hypopituitarism that should be considered in cases of growth hormone deficiency and primary amenorrhea particularly in the presence of extra pituitary malformations involving the central nervous system.

MON-714 CRISPR / Cas9 Genomic Edition of the CDH2 Gene in Zebrafish Leads to Eye and Cardiac Malformation

Introduction: The CDH2 gene encodes a transmembrane protein responsible for calcium-dependent cell-cell adhesion that participates in the process of embrionic development. Neural development is achieved by neuronal neurulation, migration and differentiation, as well as axon growth and synapse formation. During pituitary development, CDH2 was associated to the epithelium-to-mesenchymal transition, with cell migration from the marginal zone to the anterior pituitary gland, followed by terminal differentiation. Thus, a dysfunction in n-cadherins disrupts the architecture of the neural tube, cortical architecture of the embryonic brain and pituitary development. In a previous study in our laboratory, a patient was diagnosed with a homozygous variant located in the N-terminal region of CDH2 (p.Val289IIe) that culminated in congenital hypopituitarism and pituitary hypoplasia. Together, these observations indicate that cadherins, especially N-cadherin, play an indispensable role in the organization of neuroepithelial layers. Zebrafish has been widely used as a model for studies of gene functionality, as it has 70% genetic homology to humans, besides being a small animal with rapid development. Our goal was to generate a zebrafish knockout for the CDH2 gene, using CRISPR Cas9 genomic edition to study its importance during development and analyze this gene in patients with characteristics similar to those observed in zebrafish. Material and methods: Three guides were drawn for the CDH2 gene using crispor program. sgRNA, produced by in vitro transcription, and Cas9 protein were injected into one cell stage. All developmental parameters were observed under a microscope up to 96 hours post fertilization (hpf). Mortality rate were calculated at 24, 48, 72 and 96 hpf. The embryos were genotyped to confirm the deleterious allelic variant. CDH2 coding region was evaluated in 3 female siblings, born from consanguineous parents, presenting micro/anophtalmia and short stature. Exons 2 to 16 were sequenced by the Sanger method. Results: 352 eggs were injected and several deformities such as absence of somites, cardiac edema, spinal curvature, cranial malformation and microphthalmia or total absence of eyes were observed. The mortality rates were 26%, 31%, 40% and 62% at 24, 48, 72 and 96 hpf, respectively. The Sanger sequencing from DNA extracted from the whole animal presented deleterious effect classified as insertions, deletions and missense changes. No deleterious allelic variant was observed in the 15 analyzed exons in the 3 patients. Conclusion: The CDH2 gene is important for neurodevelopment and eyes formation in the zebrafish although pathogenic allelic variants in this gene was not found in the studied patients with short stature and eye abnormalities.

SAT-LB19 Is There a Need to Use Gadolinium Contrast for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?

SAT-LB19 Is There a Need to Use Gadolinium Contrast for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?

SAT-086 Pituitary Volume as a Diagnostic Measure for Determining the Etiology of Short Stature in Children: Receiver Operating Characteristic Curve Analysis and Cutoff Values

Background: It is speculated that pituitary volume (PV) is a marker of chronic growth hormone (GH) secretion. In previous studies, we determined that children with GH deficiency (GHD) and idiopathic short stature (ISS) had significantly smaller PVs than normal controls (NCs). Cutoff values for small PVs are needed to improve the clinical utility of PV in determining children who qualify for GH therapy.Objective: To define the cutoff between pathologic and nonpathologic PV in prepubertal and pubertal children with short stature (SS). Patients and Methods: The SS group was selected from the database of a pediatric endocrinology center, which was queried for siblings (SBs) aged 6–18 yrs who underwent a GH stimulation test and MRI between 2013–2019. All 77 SBs had SS, defined as 2 SDs below mean height for age, subnormal growth velocity for at least 6 months, or predicted height at least 2 inches discrepant from midparental height. The NC group was selected from the database of a neuroradiology center; these NCs consisted of 170 randomly selected subjects aged 6–18 yrs. Patients with MRI abnormalities were excluded. PVs were calculated using the ellipsoid formula (LxWxH/2). ROC curve analysis was utilized to generate cutoff values. The diagnosis of short stature was the dependent variable and PV was the independent variable. The PV with the highest Youden index was selected as the definitive cutoff for a small PV. Results: The mean (MN) and median (MD) age of SBs was 11.6 ±2.2 and 11.9 yrs, respectively, and the MN and MD age of the NCs was 12.6 ±3.4 and 13.2 yrs, respectively. The MN and MD age of prepubertal SBs (n=29) and NCs (n=58) were 9.3 ±1.2 and 9.7, and 8.6 ±1.4 and 8.6 yrs, respectively. The MN and MD age of pubertal SBs (n=48) and NCs (n=112) were 13.0 ±1.4 and 12.7, and 14.7 ±1.9 and 14.6 yrs, respectively. The difference in MN age between SBs and NCs was significant (p<0.05). For prepubertal subjects, sensitivity was 86.21% and specificity was 68.97%. The distance to corner was 0.3396, and the highest Youden index was 0.5517, corresponding to a PV of 215.02 mm3. The Area Under the Curve (AUC) was 0.8395 with a standard error of 0.0426 (p<0.001). For pubertal subjects, sensitivity was 81.25% and specificity was 79.46%. The distance to corner was 0.2781, and the highest Youden index was 0.6071, corresponding to a PV of 315.0 mm3. The AUC was 0.8460 with a standard error of 0.0337 (p<0.001). Conclusion: To our knowledge, we present the first study on the sensitivity and specificity of PV in determining the etiology of SS. Our data suggest that prepubertal patients with a PV<215.02 mm3 and pubertal patients with a PV<315.00 mm3 have small pituitary glands. Statistically calculated cutoffs are necessary to accurately diagnose pituitary hypoplasia and should be utilized to determine the etiology of SS. Future studies should include children with Tanner staging and height SDs to generate more accurate PV cutoffs.

Pathological and Incidental Findings in 403 Taiwanese Girls With Central Precocious Puberty at Initial Diagnosis.

Background: Whether girls with central precocious puberty (CPP) should undergo routine brain magnetic resonance imaging (MRI) to identify potential intracranial pathologies is controversial.Aims: To evaluate the brain MRI results of girls with CPP and identify the clinical and endocrine predictors of brain abnormalities.Methods: This retrospective study obtained data from pediatric endocrine clinics at Chang Gung Children's Hospital. From 1997 and 2017, 403 girls were consecutively diagnosed with CPP. After the exclusion of patients with a history of central nervous system (CNS) insults or associated neuropsychiatric symptom or signs, we studied the prevalence of brain abnormalities in 251 girls with CPP who received detailed MRI examinations of the hypothalamus and pituitary area. We also recorded the demographic data of the participants, including the onset of puberty; initial pubertal status; height; weight; uterus and ovary sizes; and basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol levels, and the response to GnRH stimulation test.Results: Among the 251 girls with CPP, we observed no brain alterations in 190 (75.70%), abnormalities in the hypothalamic-pituitary (H-P) area in 54 (21.51%), and abnormalities in the non-H-P area in 7 (2.79%). Among the 54 patients that had H-P lesions, we noted pathological findings related to CPP (hypothalamic hamartoma) in only one (0.4%) girl aged below 6 years old. We also identified incidental findings in the other girls with H-P lesions, including non-functioning pituitary microadenomas (12.35%), pituitary pars intermedia cysts (4.38%), Rathke's pouch cysts (1.99%), pituitary hypoplasia (1.59%), and pineal gland cysts (0.8%). The patients that had non-H-P lesions were found to have arachnoid cysts (1.59%), Chiari I malformation (0.4%), prepontine nodule (0.4%), and choroidal fissure cyst (0.4%). Of all the patients with brain lesions, 45 (73.77%) underwent regular MRI follow-up. While none of the H-P and non-H-P lesions showed progression, 19.67% of these regressed during the follow-up. None of the participants exhibited other hormonal abnormalities or underwent surgery.Conclusion: The prevalence of true pathological brain lesions related to CPP in girls without prior symptoms or signs of CNS lesions was low (0.4%). None of the girls with intracranial lesions required further intervention besides the GnRH agonist treatment. These data question the routine use of brain MRI in all girls with CPP, especially in those who are healthy without neurologic symptoms.

EP33 Pronounced dys-autonomic symptoms announcing a primary Sjögren’s syndrome

Abstract Background Sjogren syndrome (SS) is an autoimmune disease which involves the nervous system in about 20% of SS cases, whilst in 25-92% neurological symptoms may precede the onset of sicca syndrome. Methods A 65-year-old male came to our observation due to a 7-month history of near-syncope episodes, constipation, hypohidrosis, fatigue and asthenia. Past history revealed hypothyroidism due to Hashimoto's thyroiditis, under treatment with levothyroxine. Physical examination showed: temperature 36.5 °C, blood pressure 90/60 mmHg and respiration rate 20 breaths per minute. The ECG revealed sinus bradycardia with 55 beats per minute (bpm) and right bundle-branch block (RBBB). Laboratory exams showed: lymphocytopenia (WBC 9008/μL, with 90% granulocytes and 3% lymphocytes); CRP (0.3 mg/dL), ESR (20mm/hr). In order to investigate endocrine disorders, hormone tests were also performed, showing: euthyroidism (FT3 2.0 pg/mL, FT4 12.6 pg/mL, TSH 1.685 µUI/mL, Ab anti-thyroglobulin 1630.0 UI/mL, Ab anti-thyreoperoxidase 592.5 UI/mL), hypogonadotropic hypogonadism (LH 1.6 mIU/mL, FSH 2.7 mIU/mL, prolactin 15.9 ng/mL, testosterone 133 ng/dL) and normal adrenocortical function (serum cortisol 8 am 17.5 µg/dL, aldosterone 6.8 pg/dL, ACTH 8.5 pg/mL). Brain-MRI showed anterior pituitary hypoplasia. Results In order to assess a potential autonomic neuropathy, deep breathing test (E/I 1.02) , lying to standing test (R/R’ 0.95) and orthostatic hypotension tests (at 120 seconds systolic reduction was &amp;gt;20 mmHg and diastolic reduction &amp;gt;10 mmHg) were performed, all resulting pathological. ECG Holter monitoring revealed sinus bradycardia, with a mean heart rate of 55 bpm and RBBB. Holter blood pressure 24-hour monitoring showed a diurnal hypotensive profile. The echocardiogram revealed a mild mitral and tricuspid insufficiency. A paraneoplastic syndrome was also excluded by total body-CT with mean of contrast and tumor markers, which resulted normal. On a further assessment, the patient reported a 3-month history of worsening dry mouth and persistent dehydrated tongue. Signs of anisocoria in response to light stimulation, were observed as well. Tests for autoimmune diseases showed ANA (1:320 speckled pattern), Ro/SS-a (&amp;gt;240U/l) and La/SS-b (162 U/ml) antibodies. Though symptoms such as dry eyes were not reported, “Shirmer test” revealed an insufficient tear production in both eyes (RE 5 mm, LE 3 mm). The patient was discharged with the diagnosis of autonomic neuropathy most likely due to primary Sjögren’s syndrome and started therapy with Prednisone 25 mg/die and Hydroxychloroquine 200 m/bid o.d. After one month, he reported a significant improvement in symptoms such as asthenia, fatigue and dry mouth. Orthostatic hypotension symptoms were also significantly decreased and no further near-syncopal events occurred. Conclusion This case underlines the clinically importance of dys-autonomic symptoms, antecedent to the onset of sicca syndrome, and highlights the favorable response to immune-modulating therapy in the treatment of autonomic dysfunction arising from SS. Disclosures F. Masini None. K. Gjeloshi None. F. Danzo None. E. Pinotti None. L. Monaco None. G. Cuomo None.

SECONDARY ADRENAL INSUFFICIENCY MIMICKING ABDOMINAL CAUSE OF RECURRENT ABDOMINAL PAIN IN A PREPUBERTAL GIRL

Recurrent abdominal pain (RAP) in children is defined as at least three episodes of pain that occur over at least three months and affect the child's ability to perform normal activities. The prevalence of recurrent abdominal pain in a population of schoolchildren varies from 10% to even 45%. Pituitary disorders are rarely considered as causative factor in children with abdominal pain, especially in absence of midline facial defects and in case of emergency, when growth monitoring is neglected or not performed carefully. Herein we report an unusual case of RAP caused by secondary adrenal insufficiency. An 8-year-old girl was hospitalized repeatedly because of RAP. Biological parameters including white blood cell count, hemoglobin value, C-reactive protein, glucose, electrolytes were within the normal range. Low cortisol combined with low ACTH values was the clue for diagnosis. The magnetic resonance imaging (MRI) of the pituitary region revealed anterior pituitary hypoplasia and pituitary stalk interruption. To the best of our knowledge, this is the first report of child with RAP caused by pituitary disorder. Possible inherited, autoimmune and post-traumatic causative factors are discussed.

Evidence of Pituitary Hypoplasia Associated with Partial Central Diabetes Insipidus in a Young Persian Cat

Background: Congenital anomalies are an uncommon pituitary hypofunction cause associated to multiple hormone deficiencies. Congenital hyposomatotropism is often related to an inherited anomaly, characterized mainly by delayed growth. It is not uncommon to find associated thyroid-stimulating hormone and gonadotropin deficiencies. Pituitary malformation may be associated to progressive cystic lesion expansion. Central diabetes insipidus (CDI) is another rare disease associated to polyuria (PU) and polydipsia (PD) secondary to antidiuretic hormone (ADH) deficient secretion. The aim of this report is to describe a likely case of pituitary hypoplasia, associated with partial CDI in a cat.Case: A 9-month-old unneutered male Persian cat weighing 2 kg was presented due to severe polyuria and polydipsia associated with growth deficit when compared with its sibling. After clinical and laboratory evaluations during the months in which the patient was monitored, a reduced serum concentration of insulin-like growth factor-1 (IGF-1), thyroid-stimulating hormone (TSH), thyroid hormones, and testosterone was documented, confirming the diagnosis of hyposomatotropism, hypogonadism, and secondary hypothyroidism. Furthermore, therapeutic diagnosis with desmopressin revealed partial central diabetes insipidus (CDI). As the sibling showed normal development aging 13-months, a radiographic examination of the forelimb (carpus) was performed on both cats. There was lack of growth plate fusion in the patient, without any other evidence of dysgenesis, whereas complete epiphyseal closure was observed in the sibling. Despite desmopressin and levothyroxine therapeutic prescription the owners refuse further follow-up to the case.Discussion: Notwhistanding neuroimaging was not available for investigation of pituitary aspect in this particular case, the clinical symptoms added to the results of the complementary tests were consistent with pituitary hypoplasia, associated with hyposomatotropism, secondary hypothyroidism, hypogonadism, and partial CDI. Hyposomatotropism was presumably diagnosed based on the patient’s clinical characteristics, which included proportional growth delay, delayed tooth eruption, delayed growth plate fusion, associated with serum reduced IGF-1 results in comparison with its sibling. The report of low free T4 by equilibrium dialysis and of low total T4 levels, associated with low TSH levels, was considered compatible with secondary hypothyroidism. TRH stimulation test is considered the gold standard for secondary hypothyroidism diagnosis since low TSH could be secondary to assay´s low sensibility. However, normal TSH and thyroid hormone results in the sibling results ruled out this possible dismissed diagnose. The patient’s lack of sexual interest, associated with hypotestosteronemia and underdeveloped genitals (absence of penile spines and testicular hypoplasia), indicates hypogonadism. Finally, partial CDI diagnosis was demonstrated by cat´s partial ability to increase urinary specific gravity under water deprivation often made by the owners, as well as the response pattern to desmopressin therapy. Owing the lack of neurological signs expected to be associated with neoplastic or traumatic hypopituitarism etiology, hypoplasia hypothesis was raised. Quite often, patients with pituitary hypoplasia develop Rathke cleft cysts that might expand over time. In the present case, partial CDI is likely to be caused by the compression of the neurohypophysis by cyst formation secondary to adenohypophyseal hypoplasia since this kind of pituitary congenital anomaly does not justify per se neurohypophysis implications.

TOWARD NONALCOHOLIC FATTY LIVER TREATMENT; A REVIEW ON HERBAL MEDICINE TREATMENT

This study, review the nonalcoholic fatty liver treatment with emphasis on herbal medicine treatment. The accumulation of the mass of triglycerides by 5% in the liver cells of those who are not alcoholic leads to a situation called nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver is known as the most common liver disorder in the world, such that its prevalence varies from 3% to 25% in different populations of the world per race, age, sex, place of residence and lifestyle. Numerous studies have been carried out on the NAFLD and its pathological mechanism and are still ongoing. In classification of the causes of fatty liver, two general groups can be noted: (i) an effective group with indirect effects such as hypothyroidism, pituitary hypoplasia, polycystic ovarian syndrome, and sleep apnea; (ii) The other group is directly involved in the development of this disease in individuals such as abdominal obesity, metabolic syndrome and type 2 diabetes. Most patients are asymptomatic and are diagnosed by disturbed liver tests. This disease is the most common cause of liver enzymes disorder after hepatitis and chronic liver disease. In more than three-fourths of patients during a clinical examination, the increased size of liver is visible, and the most common symptom is excessive fatigue, lethargy, and pain in the upper right abdomen. The patients may complain of persistent itching, jaundice or complications caused by the increased portal pressure. If the disease leads to liver cirrhosis, hepatomegaly is seen in most cases. In most cases, the patient only finds out about the fatty liver when a regular blood test (generally liver function tests) shows a problem. Alanine aminotransferase and Aspartate aminotransferase are the most important liver enzymes, and their increase of 1.5-2 times in the tests shows the involvement of liver with this disease. Due to the key role of lipid accumulation in NAFLD progression, inhibition of lipid accumulation is a major focus of anti-NAFLD drug development. A variety of antiNAFLD agents are currently in preclinical development. Additionally, metformin, statins, and fibrates, are currently being tested as NAFLD treatments in clinical trials. This study aims to review medicinal herbs used to treat NAFLD around the world. The obtained results of the present review investigation demonstrated that 27 medicinal herbs were found that traditionally used to treat NAFLD around the world. The most parts of these plants are leaves, root, and flowers, respectively; whereas these medicinal herbs are most commonly used in countries of Asian and African such as Iran, Pakistan, India and South Africa, etc. The results demonstrated that medicinal herbs have universally used to treat NAFLD. Thus, we can consider them as alternative agents for treatment of NAFLD; nevertheless, more investigations are mandatory to elucidate the precise mechanisms and also toxicity of these plants in human subjects. Keywords: fatty liver; plant medicine; treatment; traditional medici

Auricular ossification in a patient with congenital anterior pituitary hypoplasia

Introduction: Ossification of auricular cartilage was first described in 1866 and its incidence is unclear, it is most commonly caused by trauma, frostbite, and inflammation but metabolic disorders have also been associated with it.

Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells.

Pituitary develops from oral ectoderm in contact with adjacent ventral hypothalamus. Impairment in this process results in congenital pituitary hypoplasia (CPH); however, there have been no human disease models for CPH thus far, prohibiting the elucidation of the underlying mechanisms. In this study, we established a disease model of CPH using patient-derived induced pluripotent stem cells (iPSCs) and 3D organoid technique, in which oral ectoderm and hypothalamus develop simultaneously. Interestingly, patient iPSCs with a heterozygous mutation in the orthodenticle homeobox 2 (OTX2) gene showed increased apoptosis in the pituitary progenitor cells, and the differentiation into pituitary hormone-producing cells was severely impaired. As an underlying mechanism, OTX2 in hypothalamus, not in oral ectoderm, was essential for progenitor cell maintenance by regulating LHX3 expression in oral ectoderm via FGF10 expression in the hypothalamus. Convincingly, the phenotype was reversed by the correction of the mutation, and the haploinsufficiency of OTX2 in control iPSCs revealed a similar phenotype, demonstrating that this mutation was responsible. Thus, we established an iPSC-based congenital pituitary disease model, which recapitulated interaction between hypothalamus and oral ectoderm and demonstrated the essential role of hypothalamic OTX2.

Septo-optic dysplasia with amniotic band syndrome sequence: a case report

IntroductionDe Morsier syndrome, or septo-optic dysplasia, is a rare, heterogeneous, complex condition with a highly variable phenotype. It is characterized by optic nerve hypoplasia, pituitary gland hypoplasia, and midline brain abnormalities, including absence of septum pellucidum and corpus callosum dysgenesis. Diagnosis is made clinically by the presence of any two or more features from the clinical triad.Case presentationWe report a case of a premature African newborn male baby born to nonconsanguineous parents who presented to our institution with agenesis of the septum pellucidum, unilateral optic nerve hypoplasia, and pituitary stalk hypoplasia. However, he had intact central endocrine function. He also presented with limb defects due to constricting amniotic band syndrome. Other dysmorphic features were low-set ears, microcephaly, and bilateral talipes equinovarus. He otherwise had a normal neurological examination result. Over time, he had an adequate weight gain and was managed by a multidisciplinary team.ConclusionDe Morsier syndrome still represents a diagnostic challenge, despite advances in neuroimaging and genetic studies, due to the heterogeneous nature of the disorder. This case adds to existing knowledge on the vascular pathogenesis of septo-optic dysplasia.

Septo-optic dysplasia with cerebellar hemiagenesis - a rare congenital malformation.

Septo-optic dysplasia (De morsier’s syndrome) is a rare congenital malformation of the central nervous system and represents a clinical spectrum rather than a specific entity. It is defined by any combination of pituitary hypoplasia with or without consequent panhypopituitarism,optic nerve hypoplasia and midline neurological abnormalities such as absent septum pellucidum and corpus collasum agenesis or thinning. Septo-optic dysplasia with associated cerebellar hemiagenesis is a much rarer congenital anomaly and may represent one end of this spectrum.