TSH Deficiency Research Articles

IGSF1 mutations are the most frequent genetic aetiology of thyrotropin deficiency

Thyroid-stimulating hormone deficiency (TSHD) is a rare disease. It may be isolated, secondary to abnormalities of genes involved in TSH biosynthesis, or associated with other pituitary deficits or abnormalities of genes involved in pituitary ontogenesis. Several genes are involved in thyrotroph development and function. Our aim was to determine the genetic causes of TSHD, either isolated (ITSHD) or associated with somatotroph deficiency (TSHD-GHD), in the cohort of patients from the GENHYPOPIT network. Next-generation sequencing (NGS) analyses were performed as a panel of genes on a cohort of patients with non-syndromic ITSHD or TSHGHD. The variants were classified according to the American College of Medical Genetics classification reviewed by the NGS-Diag network and correlated with the phenotype. Class 3, 4, and 5 single-nucleotide variants were checked by Sanger sequencing and copy number variants by multiplex ligation-dependent probe amplification (MLPA). A total of 64 index cases (22 ITSHD and 42 TSHD-GHD) were included in this cohort. A genetic cause was identified in 26.5% of patients, with 36.3% in the ITSHD group (variants in TSHβ and IGSF1) and 21.4% in TSHD-GHD (variants in IGSF1, TSHβ, TRHR, GH1, POU1F1, and PROP1). Among the pathogenic and likely pathogenic variants identified, 42% were in IGSF1, including six not previously reported. Our results show that IGSF1 variants represent the most frequent aetiology of TSH deficiency. Despite a systematic NGS approach and the identification of new variants, most patients remain without a molecular diagnosis. Larger scale studies, such as exome or genome studies, should be considered in the future.

RF17 | PMON24 The paradox of combined pituitary hormone deficiency and tall stature: a glimpse from exome sequencing

Abstract Introduction An intact GH-IGF-1 axis is known to be essential for proper growth. However, cases in which individuals with growth hormone deficiency (GHD) reach target height without the use of GH suggest that other mechanisms may play a role in the growth process. Out of 209 patients with hypopituitarism followed in the endocrinology clinic at HCFMUSP, 9 presented with normal stature despite GHD and hypogonadotropic hypogonadism. Among them, 1 male patient presented with tall stature. The mechanisms under growth without growth hormone are poorly understood, so we hypothesized that genetic mutations in genes related to tall stature could be a plausible explanation. The aim of the present work was to look for allelic variants in the exome that could be associated with tall stature, combined pituitary hormone deficiency and/or skeletal deformities. The index male patient presented at the age of 28 to a medical assistance due to the lack of pubertal development, leading to the diagnosis of FSH/LH and TSH deficiencies and thus treated accordingly. He was still growing even under testosterone replacement and noticed that his hand and fingers also got bigger in this period. At 32-year-old he presented to our service with a stature of 193.5cm (z score of +2.40) being out of his target height range. An arm span of 195cm was notice together with skeletal deformities such as claw toes, trigger fingers in hands and a barrel chest. At this time ACTH and GH deficiencies were diagnosed and an adult dose of GH was initiated. Over one year treatment he grew 1 cm even presenting complete closed epiphyses in hands but incomplete epiphyseal fusion in the iliac crest (Risser 4). In the skeletal X ray scoliosis, deformities in hands and feet were noticed. Pituitary MRI revealed an ectopic neurohypophysis and a reduced adenohypophysis. Whole exome sequencing was performed and allelic variants in exonic or splice site regions with frequency of less than 1% were prioritized. Out of 26 variants, 13 were classified as VUS or pathogenic in the genes PSG4, ZGPAT, LRP2, LRP5, LRP6, RYR1, REL SPAST, SDHC, EGFR, ARID3B and TGFB2, being the last 5 genes never described in 4 different populational databases (gnomAD, 1000G, ABraOM and SELAdb). Allelic variant in TGFB2 gene has been related to Marfan syndrome. Family members are having these genes in the process of being segregated. Conclusion Mutations in genes related to tall stature may be a mechanism that could explains normal growth among individuals with GHD. Presentation: Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON324 Crooke Cell Corticotroph Adenoma: A rare but Real Possibility in Children

Abstract Background Cushing disease (CD) is uncommon in the pediatric population and is usually caused by benign pituitary corticotroph microadenomas. In some adults with CD, Crooke cell adenoma (CCA), a more aggressive histologic variant of corticotroph adenomas, has been described. CCA has rarely been reported in children as the etiology of CD and its course is not well described. Objectives To report a pediatric case of CCA, the youngest to our knowledge Case An 11-year-old African American female presented to the endocrinology clinic with concerns for diabetes, excessive weight gain and linear growth arrest. Workup for possible etiology showed: midnight salivary cortisol 0.924 (normal < 0.112 µg/dL), ACTH 119(6-48 pg/mL), morning cortisol 8.5 (normal < 1.8 µg/dL) post 1 mg dexamethasone mg/dL, consistent with the diagnosis of CD. Magnetic resonance imaging (MRI) showed a 4 mm pituitary microadenoma in the left anterior side of the adenohypophysis for which she underwent endoscopic endonasal transsphenoidal resection. Histopathologic examination revealed pituitary adenomatous tissue consisting of a uniform population of basophilic cells with granular cytoplasm, arranged in trabeculae and small nests with bundles encircling the nuclei, findings pathognomonic of CCA. Given persistence of hypercortisolemia, another transsphenoidal gross total resection of residual adenomatous tissue was performed 4 months later. This led to resolution of CD as evidenced by weight loss and linear growth. Twelve months following the second surgery, the patient experienced rapid weight gain and a decelerated linear growth accompanied by pubertal arrest. Another pituitary MRI showed a recurrent left sided adenoma (8×8×7 mm). Biochemical investigation this time again showed elevated midnight salivary cortisol and 24- hour urine free cortisol (UFC). In addition, AM cortisol was unsuppressed following 1 mg overnight dexamethasone administration. In response, repeat transsphenoidal gross total resection was performed, however residual microscopic disease in the cavernous sinus wall was highly suspected intraoperatively. A spine MRI did not show disseminated disease. Despite this, hypercortisolemia persisted both clinically and biochemically. The patient subsequently underwent proton beam radiation therapy in combination with adjuvant adrenolytic therapy with mitotane. The patient responded to these interventions with normalization of 24-hour UFC, resumption of linear growth, and pubertal progression. The treatment course was complicated by the development of isolated TSH deficiency requiring thyroid hormone replacement. Conclusion CCA is an aggressive entity described in the adult literature as a cause of CD. The current report adds to the limited pediatric cases of this disease. CCA can be equally aggressive in children and refractory to surgical treatment. Here, we show that it may respond to proton beam radiation and adrenolytic therapy. Pediatric endocrinologists should be aware of the rare occurrence of CCA in children and tailor treatment accordingly using a multi-disciplinary approach. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Central Diabetes Insipidus in Children and Adolescents: Twenty-Six Year Experience from a Single Centre.

Introduction Paediatric cohorts of central diabetes insipidus (CDI) have shown varying prevalence for different causes of CDI. The objective of this study was to determine the causes of CDI and long-term outcome in children and adolescents from a Tertiary Paediatric Endocrinology unit. Methods The clinic database was searched to identify patients with CDI managed between 1993 and 2019. Relevant clinical information was collected from patient records. Results A total of 138 CDI patients, median age 6 years (range <1–18) at presentation, were identified. Principal CDI aetiologies were craniopharyngioma (n = 44), acute central nervous system (CNS) insult (n = 33), germinoma (n = 15), postneurosurgery (indication other than craniopharyngioma and germinoma, n = 20), midline CNS malformation (n = 14), Langerhans cell histiocytosis (n = 5), and familial (n = 2). Idiopathic CDI in this cohort was infrequent (n = 5). Patients with CNS malformations/infections presented with CDI at a younger age compared to patients with CNS tumours (p < 0.0001). Five patients, initially presenting as idiopathic CDI, were subsequently diagnosed with germinoma after a median interval of 3.3 years. All patients with CDI related to craniopharyngioma and nearly all (87%) patients with CDI related to germinoma had concomitant GH, ACTH, and TSH deficiency. The majority of patients who manifested CDI due to acute CNS insult either deceased (30%) or had transient CDI (33.3%). Conclusion Surgery for craniopharyngioma was the most common underlying aetiology of CDI with ubiquitous occurrence of panhypopituitarism in these patients. Manifestation of CDI in patients with acute CNS insult carries poor prognosis. We affirm that neuroimaging assessment in idiopathic CDI should be continued beyond 3 years from diagnosis as a significant number of patients exhibited progression of infundibular thickening 3 years post-CDI diagnosis.

Abstract 94: Efficacy of cabergoline treatment in men with giant prolactinomas

Introduction: Giant prolactinomas in males are rare tumours in whom outcome data is scarce.Aims and Objectives: To evaluate the outcomes of therapy in men with ‘giant prolactinomas’ (>4 cm).Results: Of twenty-five males with macroprolactinoma following up in the Endocrinology Clinic; ten fulfilled the criteria of Giant Prolactinoma and were included in this retrospective study. The mean age was 34.2±12.67 years. Headache (n=10) and visual field defects (n=8) followed by hypogonadal symptoms (n=8) were the common presenting symptoms. A significant decrease of the Prolactin (PRL) values was observed in all patients (6420±1343.3 to 97.5±1.72 ng/dl; p= 0·0005). Persistent normalization of PRL levels was achieved in 7/10 patients. Significant tumour shrinkage (5±0.40 to 2.7±0.28 cm, p = 0·02) was achieved in 8/10 patients, with a volume reduction > 90% in three, >50% in four and >25% in one patient.Gonadotropin deficiency (n=9); TSH deficiency (n=4) and Cortisol deficiency (n=4) were uncovered on initial laboratory evaluation. The gonadotropin axis recovered in 1/9 and cortisol axis in 3/4 deficient subjects after normoprolactinaemia was achieved. The thyrotropin axis was affected irreversibly.Discussion and Conclusion: In male subjects with giant prolactinomas, recovery in other pituitary axes did not occur in spite of normalizing PRL levels and achieving tumour shrinkage.

Proton Stereotactic Radiotherapy for Treatment of Nelson's Syndrome

Nelson's syndrome is a rare disorder that may arise as a complication of treating Cushing's disease through bilateral adrenalectomy. It is characterized by growth of remaining pituitary adenoma and elevation of adrenocorticotropic hormone (ACTH) levels. Prior studies have established radiation therapy (RT) as a method of treating Nelson's syndrome. In this study, we evaluated the efficacy of proton stereotactic radiosurgery (PSRS) on decreasing ACTH levels and achieving disease remission in patients with Nelson's syndrome treated with SRS.A retrospective analysis of eight patients with Nelson's syndrome who received PSRS between 2007 and 2017 at our institution was conducted. All patients previously underwent bilateral adrenalectomy for treatment of Cushing's disease. Patients received PSRS at a total dose of 15 or 20 Gy(RBE) delivered in one fraction. The median clinical target volume was 5.7 cc (range 3.7-9.0 cc). ACTH levels, disease status, and post-treatment complications were followed post-SRS to assess for endocrine remission.The median follow-up was 80 months (range 35-126 months) from the end of SRS treatment. The median ACTH level decreased from 761.5 pg/mL pre-SRS to 38 pg/mL post-SRS at time of latest follow-up. Endocrine remission was achieved among six patients (75%) at a median time of 47 months (range 12 -126 months) from SRS. Three patients (38%) developed pituitary deficits (two with TSH and gonadal deficiency and one with pan-pituitary deficiency) post-SRS.SRS can be an effective treatment to achieve endocrine remission in patients with Nelson's syndrome. SRS can lead to pituitary deficits in some patients and longer follow-up is warranted to assess long-term disease control and treatment toxicity.D.W. Kim: None. G. Lee: None. E. Cai: None. B. Swearingen: None. P.H. Chapman: None. M.R. Bussiere: Consultant; American College of Radiology. A. Klibanski: None. J.S. Loeffler: None. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital.

Diagnosis of severe growth hormone deficiency in the newborn

OBJECTIVE Severe neonatal growth hormone deficiency (GHD) can cause recurrent hypoglycaemia. Early diagnosis is warranted. The aim of the study was to analyse the GH content in screening cards of 25 affected and 281 healthy newborns. PATIENTS AND MEASUREMENTS A total of 110 screening cards from ill newborns were sent to us for measuring GH content by a highly sensitive GH ELISA. Clinical information was obtainable in 61 cases. Severe GHD was defined by the presence of recurrent hypoglycaemia with a significant pituitary malformation or two additional pituitary hormone deficiencies. Screening cards from 281 healthy newborns (34.0-37.9 weeks) were prospectively analysed. RESULTS In 25 newborns (5 preterm), the definition of severe GHD was fulfilled based on recurrent hypoglycaemia in combination with malformation of the pituitary or midline structures in 21 cases and combined TSH and ACTH deficiency in four cases. The median GH concentration of those affected with severe GHD was 3.9 µg/L (range: 1.1-11.8), significantly below the previously reported reference range (P < .001). A GH concentration of 7 µg/L was confirmed as the cut-off for term newborns with the best accuracy (90.0% sensitivity and 98.7% specificity). The 95% reference range for healthy preterm newborns (n = 151) was 7.6-47.1 µg/L (median: 20.3 µg/L). CONCLUSIONS A GH content <7.0 µg/L in the newborn screening card confirms severe GHD with high accuracy. In preterm newborns, the lower limit of the reference interval was 0.6 µg/L higher than in term newborns. The newborn screening card is a valuable source for the very early diagnosis of GH deficiency.

Two Cases of Anti-PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome

Abstract Background: Anti-pituitary-specific transcription factor 1 (PIT-1) hypophysitis (anti-PIT-1 antibody syndrome) is a newly defined clinical entity, demonstrating an adult-onset hypopituitarism, and is a thymoma-associated autoimmune disease characterized by acquired GH, PRL, and TSH deficiencies due to autoimmunity against PIT-1 (1, 2). This disease is defined by an acquired specific GH, PRL, and TSH deficiencies and the presence of circulating anti-PIT-1 antibody and/or PIT-1-specific T cells (2). As the etiology, ectopic expression of PIT-1 in thymoma plays a causal role in the development of the disease (3); however, it is unknown whether this disease is involved in other conditions. Here, we report two PIT-1 hypophysitis cases, exhibiting as a form of paraneoplastic syndrome with malignancies other than thymoma. Clinical Case: A 79-year-old woman (case 1) and an 86-year-old man (case 2) were referred to us on suspicion of anti-PIT-1 hypophysitis because of acquired GH, PRL, and TSH deficiencies. In both patients, the endocrinological evaluation revealed extremely low basal levels and blunted responses of GH, PRL, and TSH to the provocative stimuli. In contrast, the secretion of HPA and HPG axis were preserved in both patients. Magnetic resonance imaging of the pituitary gland showed slight atrophy in case 1 and normal size in case 2. Interestingly, computed tomography imaging revealed no evidence for thymomas in both patients. On the other hand, case 1 was complicated with diffuse large B-cell lymphoma (DLBCL) of the bladder with multiple bilateral cervicals, axillary, para-aorta, and internal and external peri iliac lymphadenopathies. Case 2 was diagnosed with malignancy with multiple metastases of unknown origin with para-aortic and para-gastric lymphadenopathies, and vertebral body infiltrates. Because circulating anti-PIT-1 antibody was detected, both patients were diagnosed with anti-PIT-1 hypophysitis. Circulating PIT-1-reactive T cells were detected in case 1 using Enzyme-Linked Immunospot assay. Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL tissue of case 1, while DLBCL tissues derived from control patients without anti-PIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of the situation of the best supportive care. Conclusion: These data show that anti-PIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1- reactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma (3). Thus, anti-PIT-1 hypophysitis is defined as a form of paraneoplastic syndrome. Reference: (1) J Clin Invest. 2011;121(1):113-119., (2) Endocr Rev. 2020;41(2)., (3) Sci Rep. 2017;7:43060.

SIX3 Variant Causes Pituitary Stalk Interruption Syndrome and Combined Pituitary Hormone Deficiency

The genetic basis for congenital hypopituitarism and related disorders is beginning to emerge, and over 30 causal genes have been identified. Mutations in some of these genes can also cause holoprosencephaly (HPE) or septo-optic dysplasia. SIX3 is a homeodomain protein expressed in the developing brain, pituitary gland, and eye. Heterozygous mutations in SIX3 cause variable HPE in humans and mice. We identified two children with neonatal GH and TSH deficiency and stalk interruption who were doubly heterozygous for rare, likely deleterious variants in SIX3 and POU1F1. Functional studies demonstrated that both variants are disruptive. We used Six3 and Pou1f1 loss of function mice to assess the genetic interaction between Six3 and Pou1f1. Six3 heterozygotes have variable pituitary gland dysmorphology, while Pou1f1 heterozygotes are normal. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease. To understand the role of SIX3 in pituitary and hypothalamic development, we used Prop1-cre and Nkx2.1-cre to delete Six3. Disruption of Six3 expression in Rathke’s pouch caused poor activation of Lhx3 expression and arrested anterior pituitary development. The Nkx2.1-cre, Six3flox/flox embryos had no evidence of infundibulum evagination and failed to induce FGF and BMP signaling, which normally drive expansion of Rathke’s pouch. By E11.5 cells in Rathke’s pouch underwent apoptosis. The Nkx2.1-cre, Six3flox/flox embryos failed to activate expression of Lhx2 and Tbx3 in the neural ectoderm. These embryos had elevated CCND1, MYCN, and Axin2 expression in the area of the presumptive infundibulum. This indicates that SIX3 is necessary to repress cell proliferation and Wnt/beta-catenin signals to promote formation of the pituitary stalk. Thus, Six3 has essential roles in both the neural and oral ectoderm for hypothalamic and pituitary development, respectively. Heterozygous loss of function variants in SIX3 could be a contributor to multiple pituitary hormone deficiencies in children, especially if there are associated craniofacial abnormalities or PSIS.

Pituitary Macroadenoma Masked by Iatrogenic Adrenal Insufficiency: A Diagnostic Blind Spot

Background: Exogenous steroid use is the most common cause of central adrenal insufficiency. Depending on the duration and strength used, it may take months to years for the hypothalamic-pituitary-adrenal (HPA) axis to recover after the steroid is stopped. We report a case of iatrogenic hypoadrenalism with persistent suppression of the HPA axis for 13 years, discovered later to be due to a second pathology. Case: A 48 year old lady presented in 2005 with weight gain of 20 kg over 1 year and florid Cushingoid features. 9AM cortisol was undetectable (<12 nmol/L). History taking revealed use of oral dexamethasone at various dosages over the past 9 years for her knee pains. A diagnosis of iatrogenic adrenal insufficiency was made. She was started on hydrocortisone replacement, and was advised to stop the over-the-counter steroids. By 2011 her short Synacthen test (SST) showed much improved functioning of the HPA axis (cortisol 182 (0 min) -> 329 (30 min) -> 408 nmol/L (60 min) [N peak>500 nmol/L]), and she was back to her usual body weight. However, subsequent monitoring revealed declining trend of 9AM cortisol from 135 nmol/L (2013) -> 99 nmol/L (2014) -> 57 nmol/L (2015) -> 64 nmol/L (2016) -> 18 nmol/L (2017) [N 166–507 nmol/L]. Hydrocortisone compliance and abstinence from exogenous steroids was confirmed with the patient. The ongoing hypofunction of the HPA axis was continually attributed by multiple physicians to her history of prolonged use of dexamethasone. In 2018, at the age of 60, the lady presented with new onset headaches, blurred vision, and bitemporal hemianopia for 3 months. MRI showed a 1.8x1.8x3.5 cm (WxAPxH) pituitary mass with suprasellar extension compressing the optic chiasm. Blood tests revealed panhypopituitarism: SST cortisol 17 -> 59 -> 49 nmol/L, ACTH 2.7 pmol/L [N <10.1 pmol/L]; fT4 9.5 pmol/L [N 12–22 pmol/L], TSH 0.97 mIU/L [N 0.27–4.2 mIU/L]; LH <0.1 IU/L, FSH 0.52 IU/L (menopause at age of 48); IGF-1 27 µg/L [N 41–279 µg/L]; prolactin 17 mIU/L [N 102–496 mIU/L]. After partial excision of the mass her vision improved, but remained dependent on hydrocortisone and thyroxine supplements. The lesion was pathologically proven to be a pituitary macroadenoma. Discussion: This case presents the uncommon course of a patient who had almost recovered from iatrogenic hypoadrenalism, only to lapse back into worsened central adrenal insufficiency, as part of panhypopituitarism related to an undiagnosed pituitary mass. In retrospect, the unusually protracted state of hypocortisolemia and the atypical waxing and waning HPA axis should have alerted one to consider alternative etiologies at work. As LH-FSH and GH deficiencies commonly develop before ACTH and TSH deficiencies in most pituitary macroadenomas, a lower threshold for testing the other anterior pituitary hormones followed by imaging of the pituitary could have picked up the tumor earlier in this patient.

Identification of FOXA2 and PNPLA6 Among Other Genes, as a Potential Risk for Pituitary Hormone Deficiency

Abstract Pituitary hormone deficiency or hypopituitarism is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases. We sought to identify the cause of hypopituitarism in 171 unrelated patients diagnosed with or without extra-pituitary manifestations that were recruited from several Argentinean medical centers. We conducted panel sequencing, and identified among other genes and variants, de novo heterozygous mutations in FOXA2 and PNPLA6. FOXA2 is a transcription factor member of the forkhead class of DNA-binding proteins, involved in the early development of multiple tissues. FOXA2 is highly expressed throughout the developing hypothalamic-pituitary axis, and regulates GLI2, SHH and NKX2-2 expression. Mutations of FOXA2 have been linked to combined pituitary hormone deficiency (CPHD) in some cases with extra-pituitary phenotypes including hyperinsulinism or gastrointestinal malformations. We found two patients with CPHD and rare FOXA2 variants. Case 1 had GHD, anterior pituitary hypoplasia, mammary hypertelorism and digital anomalies and a heterozygous variant FOXA2 p.Arg228Ser, predicted to be pathogenic. Case 2 had GH and TSH deficiency, craniofacial anomalies and neurodevelopmental delay, and a novel, stop codon mutation FOXA2 p.Ser229* and an heterozygous GLI1 variant (p.Asp1048Asn). Both FOXA2 variants are located within the forkhead domain which may affect the DNA binding ability. We suspect they are likely damaging based on the literature, the in-silico prediction, and their absence in GnomAD. PNPLA6 is a conserved lysophospholipase involved in maintaining nervous system integrity. Mutations in PNPLA6 have been identified in a broad spectrum from pure ataxia to rare neuroendocrine conditions including Gordon Holmes and Oliver McFarlane syndromes. Here, we identified two de novo heterozygous variants in PNPLA6 in children with CPHD. Variant p.W1039R was found in a patient with CPHD, intellectual disability and visual problems. A second variant (p.T1115P) was identified in a 10-year-old girl with CPHD, retinitis pigmentosa and neurodevelopmental delay. According to modelling studies of the protein structure, both variants are expected to be critical for the activity of the NTE as they are located in close proximity to the protein’s catalytic pocket. It is likely that these variants may contribute to our patient’s phenotype. However, as most reported PNPLA6 variants in the literature were found in homozygosity or compound heterozygosity, additional studies are necessary to draw more definitive genotype-phenotype correlations. In summary, in this work we were able to expand our knowledge of pituitary target genes for genetic diagnosis for CH.

Immune checkpoint inhibitor related hypophysitis: diagnostic criteria and recovery patterns.

Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6–3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.

POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature.

POU1F1 mutations are prevalent in Indian CPHD cohorts. Genotype-phenotype correlation is not well-studied. To describe phenotypic and genotypic spectrum of POU1F1 mutations in our CPHD cohort and present systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in world literature. Retrospective study of POU1F1 mutation-positive patients from a western-Indian center. PRISMA guidelines based pubmed search of published literature of all mutation-positive patients. Our cohort had 15 POU1F1 mutation-positive patients (9 index, 6 relatives). All had severe GH, TSH and prolactin deficiencies (GHD, TSHD and PD). TSHD was diagnosed earliest followed by GHD (median ages: TSHD-6months, GHD-3years), while PD was more variable. Two sisters had central precocious puberty at 7years of age. Pubic hair was deficient in all post-pubertal patients (females: P1-P2, males: P3-P4). Splice-site/intronic/frameshift mutations were most common, while missense/nonsense mutations were less frequent (33%). Review of world literature yielded 114 patients (82 index patients) from 58 studies. GHD was present in all patients. TSHD was spared in 12.5% and PD in 4.4% patients. Missense/nonsense mutations accounted for 75% of spectrum. Phenotype-genotype analysis revealed higher mean peak-GH levels (1.1 vs 0.2ng/ml, p = 0.008) and lower prevalence of anterior-pituitary hypoplasia (63.6% vs 86.3%, p = 0.03) in patients with heterozygous than homozygous and compound heterozygous mutations. We present largest series of POU1F1 mutation-positive patients. Precocious puberty and defective pubarche are lesser-appreciated phenotypic features. Our mutation spectrum is different from that of world literature. Patients with heterozygous mutations have milder phenotype.

Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism.

Hypopituitarism is a disorder characterized by insufficient secretion of one or more pituitary hormones. New etiologies of hypopituitarism have been recently described, including head trauma, cerebral hemorrhage, and drug-induced hypophysitis. The investigation of patients with these new disorders, in addition to advances in diagnosis and treatment of hypopituitarism, has increased the prevalence of this condition. Pituitary hormone deficiencies can induce significant clinical changes with consequent increased morbidity and mortality rates, while hormone replacement based on current guidelines protects these patients. In this review, we will first discuss the different etiologies of hypopituitarism and then address one by one the clinical aspects, diagnostic evaluation, and therapeutic options for deficiencies of TSH, ACTH, gonadotropin, and GH. Finally, we will detail the hormonal interactions that occur during replacement of pituitary hormones.

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome.

Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. The pituitary gland is a central regulator of growth, metabolism, and reproduction. The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin. The posterior pituitary hormone secretes antidiuretic hormone and oxytocin.Epidemiology: The incidence is 1 in 4,000–1 in 10,000. The majority of CH cases are sporadic; however, a small number of familial cases have been identified. In the latter, a molecular basis has frequently been identified. Between 80–90% of CH cases remain unsolved in terms of molecular genetics.Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland. Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8. Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation.Clinical manifestations: Genotype-phenotype correlations are difficult to establish. There is a high phenotypic variability associated with different genetic mutations. The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies.Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests. However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations. Once a hormone deficit is confirmed, hormone replacement should be started. If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency. This review aims to give an overview of CH including management of this complex condition.

Somatostatin receptor ligands induce TSH deficiency in thyrotropin-secreting pituitary adenoma.

Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL. Retrospective study. Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency. Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency. SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.

Two Cases of anti–PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome not Associated With Thymoma

Anti–pituitary-specific transcription factor 1 (PIT-1) hypophysitis (anti–PIT-1 antibody syndrome) is a thymoma-associated autoimmune disease characterized by acquired growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) deficiencies due to autoimmunity against PIT-1. Ectopic expression of PIT-1 in the thymoma plays a causal role in development of the disease. Here, we report 2 cases of anti–PIT-1 hypophysitis exhibiting as a form of paraneoplastic syndrome with conditions other than thymoma. A 79-year-old woman (case 1) and an 86-year-old man (case 2) were referred with a suspicion of anti–PIT-1 hypophysitis because of acquired GH, PRL, and TSH deficiencies. Case 1 was complicated by diffuse large B-cell lymphoma (DLBCL) of the bladder and case 2 was diagnosed with malignancy with multiple metastases of unknown origin. Because circulating anti–PIT-1 antibody was detected, both patients were diagnosed with anti–PIT-1 hypophysitis. Circulating PIT-1–reactive T cells were detected in case 1 via enzyme-linked immunospot (ELISPOT) assay. Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL cells of case 1, whereas DLBCL tissues derived from patients without anti–PIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of best supportive care was under way. These data show that anti–PIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1–reactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma. Thus, anti–PIT-1 hypophysitis is defined as a form of paraneoplastic syndrome.

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

Background and Aims&#x0D; 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.&#x0D; Case Reports&#x0D; 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.&#x0D; 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.&#x0D; Discussion&#x0D; 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.&#x0D; Conclusions&#x0D; 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.

Identification of Novel Missense Mutations of the TSH-β Subunit Gene in Pediatric Patients with Congenital Central Hypothyroidism

Background: Congenital central hypothyroidism (CCH) is a rare autosomal recessive disease caused by mutations in the thyroid-stimulating hormone β subunit (TSHβ) gene. Since patients with CCH do not experience increased serum levels of TSH, the diagnosis is usually delayed, which leads to negative consequences in the neonatal TSH screening. Genetic diagnostic studies enable us to identify affected relatives at high risk for rapid diagnosis and treatment of the disorder. Objectives: This study aimed to investigate genetic variations in the TSHβ gene for the first time in Iranian patients with CCH. Methods: Seven children affected by congenital TSH-deficient hypothyroidism were investigated for mutations in TSHβ. Variable TSH levels in these patients ranged from low values for diagnosis to significant values, so central hypothyroidism was assumed due to mutations in the TSHβ gene. Results: We identified two novel heterozygous (F11Y and G106R) and one homozygous (T14A) missense mutations in the coding sequence of exons 2 and 3. One of the new heterozygous mutations (F11Y) and a homozygous (T14A) missense mutation were found in exon 2 of the TSHß-subunit gene. The novel mutation G106R in exon 3 was found in three pediatric patients with congenital hypothyroidism. c.40A&gt;G (T14A, rs10776792) appears to be the most common genetic variation associated with TSH deficiency. The others were c.32T&gt;A in exon 2 and c.316G&gt;C in exon 3, which resulted in a change from phenylalanine to tyrosine (p.F11Y) and glycine to arginine (G106R), respectively. Conclusions: The identification of these mutations for the first time in Iranian patients suggests that CCH is more common than previously recognized, and the TSHβ gene may be the mutational hot spot.

BASELINE CHARACTERISTICS OF PATIENTS WITH GROWTH HORMONE DEFICIENCY

Objective: The aim of this study was to describe the characteristics and the aetiological profile of patients with growth hormone deficiency (GHD) Material and Method: Among randomly selected 320 cases with short stature with a height SDS&lt;-3SD, 203 patients with diagnosis of GHD were evaluated with respect to their characteristics at diagnosis. Results: 86 patients (42.4%) had idiopathic GHD, 79 patients (39%) had congenital GHD, 14 patients (6.9%) had defined syndromes with GHD and 10 patients (5%) had acquired GHD. Number of patients with isolated GHD was 154 (81.5%) and with multiple pituitary hormone deficiency (MPHD) was 35 (18.5%) among classified cases. The most common accompanying hormone deficiency was TSH deficiency in GHD aetiologies with MPHD. Hypophyseal pathologies were most commonly seen in congenital and acquired GHD cases. Noonan syndrome was the most common syndrome with an accompanying GHD. The bone age delay was found to be over 2 years in congenital GHD. The mean IGF-1 SD score and the mean peak growth hormone stimulation tests’ values were significantly low in congenital GHD. Conclusions: Precise assessment of auxological, clinical and laboratory data could provide substantial value in the evaluation of severely short statured children with GHD.&nbsp;