Anterior Pituitary Hypoplasia Research Articles

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by an absent or ectopic posterior pituitary, absent or interrupted pituitary stalk and anterior pituitary hypoplasia on magnetic resonance imaging (MRI), as well in some cases a range of heterogeneous somatic anomalies. The triad can be incomplete. Here, we performed exome sequencing on 16 sporadic patients, aged 0.4 to 13.7 years diagnosed with isolated or complex PSIS. Growth hormone deficiency was isolated in 10 cases, or associated with thyrotropin deficiency in 6 others (isolated (2 cases), associated with adrenocorticotropin deficiency (1 case), gonadotropins deficiency (1 case), or multiple deficiencies (2 cases)). Additional phenotypic anomalies were present in six cases (37.5%) including four with ophthalmic disorders. In 13 patients variants were identified that may contribute to the phenotype. However, only a single individual carried a variant classified as pathogenic. This child presented with the typical clinical presentation of Okur-Chung neurodevelopmental syndrome due to a CSNK2A1 missense variant. We also identified variants in the holoprosencephaly associated genes GLI2 and PTCH1. A likely pathogenic novel splice site variant in the GLI2 gene was observed in a child with PSIS and megacisterna magna. In the remaining 11 cases 26 variants in genes associated with pituitary development or function were identified and were classified of unknown significance. Compared with syndromic forms the diagnostic yield in the isolated forms of PSIS is low. Although we identified rare or novel missense variants in several hypogonadotropic hypogonadism genes (e.g. FGF17, HS6ST1, KISS1R, CHD7, IL17RD) definitively linking them to the PSIS phenotype is premature. A major challenge remains to identify pathogenic variants in cases with isolated PSIS.

FRI325 Pituitary Stalk Interruption Syndrome Presenting As Short Stature: A Case Report

Abstract Disclosure: S. Ravindra: None. S. Tirupati: None. Background: Pituitary stalk interruption syndrome (PSIS) is a rare congenital pituitary anatomical defect that leads to a variable degree of pituitary hormone deficiency. The classic neuroimaging findings of this condition include thin or interrupted stalk, absent or ectopic posterior pituitary, and hypoplastic anterior pituitary gland. The reported incidence of PSIS is 0.5 per 1,00,000 live births. The exact pathophysiology of this syndrome is not fully understood, but chromosomal microdeletions and perinatal asphyxia have some established roles in the literature as primary miscreants. Here we report a case of an adolescent male child who presented with complaints of short stature and absent secondary sexual characters development, diagnosed with PSIS following an MRI. Clinical Case: A 16-year-old male child was referred to the endocrinology department for the evaluation of short stature and delayed secondary sexual character development. This patient was born out of a non-consanguinous marriage and delivered at term by the vaginal route, with no other significant perinatal or family history. Psychomotor milestones were attained appropriately as per age but had poor linear growth. On examination, he had short stature - height 146cms (-2.7 SDS), weight: 53.5kg BMI: 23.5 Kg/m2 with normal vitals. Head-to-toe examination revealed immature facies, deep-seated eyes, broad nasal bridge, bilateral lipomastia, high-pitched voice, Tanner stage: A1P1, SPL:4cms, the testicular volume of 3cc bilaterally, with rest of the system-wise examinations being normal. Routine laboratory investigations (CBC, RFT, LFT, Electrolytes) were within normal limits. Bone age: 13years. The hormonal assessment showed central hypothyroidism, hypocortisolemia, and GH insufficiency, with pre-pubertal gonadotropin levels- suggestive of pan-hypopituitarism (Table 1). MRI pituitary showed anterior pituitary hypoplasia with interrupted stalk, and ectopic posterior pituitary, with no other brain anomalies which is consistent with the diagnosis of PSIS. The patient was initiated on hormone replacement therapy, currently taking hydrocortisone, growth hormone, levothyroxine, and testosterone. Conclusion: PSIS is a rare condition, that can present with various spectrum of clinical features. Signs and symptoms may not be evident in the neonatal and infancy period, therefore diagnosis is often delayed. Early diagnosis and treatment are crucial for preventing adverse effects of long-term hormonal deficiencies and improving the quality of life. Presentation: Friday, June 16, 2023

Pituitary Stem Interruption Syndrome (SITP) diagnosed in childhood in a case at the Center Hospitalier Universitaire de Libreville (CHUL)

Interrupted pituitary stalk syndrome (PITS) is a hypothalamic-pituitary morphological abnormality characterized by a slender or absent pituitary stalk, anterior pituitary hypoplasia, and ectopic posterior pituitary. Hormonal assessment and imaging are crucial for the diagnosis, early management can improve the child's stature prognosis. We report the case of an 8-year-old child seen in endocrinology consultation for growth retardation. His medical history revealed acute fetal distress at birth, neonatal jaundice, and numerous consultations in early childhood for this anomaly. The clinical examination found a statural delay of -3DS, bilateral cryptorchidism, with small testicles. The hormonal balance found multiple pituitary deficits and Magnetic Resonance Imaging showed an absence of the pituitary stalk, anterior pituitary hypoplasia, and ectopia of the posterior pituitary. Deficient hormone supplementation was instituted. This case relates the typical picture of hypopituitarism by the absence of the pituitary stalk in a context where the disease is probably underdiagnosed due to lack of technical support in sub-Saharan Africa and little known. This explains the diagnostic error in our case, moreover, it allows us to pay particular attention to the meticulous monitoring of the growth of children who have presented perinatal anomalies, and the multidisciplinary exploration in the event of growth disorders.

POU1F1/Pou1f1 c.143-83A > G Variant Disrupts the Branch Site in Pre-mRNA and Leads to Dwarfism.

POU Class 1 Homeobox1 (POU1F1/Pou1f1) is a well-established pituitary-specific transcription factor, and causes, when mutated, combined pituitary hormone deficiency in humans and mice. POU1F1/Pou1f1 has 2 isoforms: the alpha and beta isoforms. Recently, pathogenic variants in the unique coding region of the beta isoform (beta domain) and the intron near the exon-intron boundary for the beta domain were reported, although their functional consequences remain obscure. In this study, we generated mice carrying the Pou1f1 c.143-83A>G substitution that recapitulates the human intronic variant near the exon-intron boundary for the beta domain. Homozygous mice showed postnatal growth failure, with an average body weight that was 35% of wild-type littermates at 12 weeks, which was accompanied by anterior pituitary hypoplasia and deficiency of circulating insulin-like growth factor 1 and thyroxine. The results of RNA-seq analysis of the pituitary gland were consistent with reduction of somatotrophs, and this was confirmed immunohistochemically. Reverse transcription polymerase chain reaction of pituitary Pou1f1 mRNA showed abnormal splicing in homozygous mice, with a decrease in the alpha isoform, an increase in the beta isoform, and the emergence of the exon-skipped transcript. We further characterized artificial variants in or near the beta domain, which were candidate positions of the branch site in pre-mRNA, using cultured cell-basis analysis and found that only c.143-83A>G produced transcripts similar to the mice model. Our report is the first to show that the c.143-83A>G variant leads to splicing disruption and causes morphological and functional abnormalities in the pituitary gland. Furthermore, our mice will contribute understanding the role of POU1F1/Pou1f1 transcripts in pituitary development.

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

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. To identify patients with PSIS and obesity or overweight, describe their phenotype, and compare them with patients with PSIS without overweight/obesity. 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. 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). 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.

Pituitary Stalk Interruption Syndrome in a Newborn with Encephalopathy: A Case Report

Background: Pituitary Stalk Interruption Syndrome is a rare midline brain anomaly involving the pituitary gland that leads to a variable degree of pituitary hypofunction with a classic neuroimaging finding of the ectopic posterior pituitary, thin or absent pituitary stalk, and anterior pituitary hypoplasia. Case Presentation: We present the case of a term newborn who developed encephalopathy and respiratory distress during the neonatal period and was later diagnosed with Pituitary Stalk Interruption Syndrome. Conclusion: Genetic defects have been identified in 5% of cases, and at times there are associated extra pituitary malformations. In spite of being a welldescribed syndrome, a detailed description of its neonatal presentation and course is lacking in the literature.

Abstract #1176767: A Rare Case of Incidental Ectopic Posterior Pituitary in an Adult

Ectopic posterior pituitary (EPP) is a rare anomaly that is usually diagnosed in childhood and typically associated with aberrant pituitary stalk development, anterior pituitary hypoplasia and functional deficits, and craniofacial abnormalities. We present a case of incidental EPP diagnosed in an adult patient. A 57-year-old female underwent MRI for evaluation of headache and right ocular pain. A normal-sized anterior pituitary was present in the sella turcica, but the pituitary stalk could not be visualized and T1 weighted high-signal corresponding to the neurohypophysis was ectopically adjacent to the superior margin of the anterior pituitary. The patient reported an unremarkable gestation and birth, was of slightly below average stature for a woman in the United States (163 cm, 64 in), had two children and no problems with infertility, and denied polyuria and nocturia. She reported an automobile accident with head trauma at age 20 years, though she was not informed of head imaging abnormalities. Primary hypothyroidism was well compensated on supplemental thyroxine, and gonadotropins were appropriately elevated for postmenopausal status. Measurements of IGF-1 and prolactin were within their respective laboratory reference ranges, but 8 AM cortisol (0.9 μg/dL, expected > 15) and ACTH level (< 5 pg/mL, 10-65) indicated isolated secondary adrenal insufficiency (AI). Diagnosis of AI was confirmed by a 250 μg Cosyntropin™ stimulation test (30 min stimulated cortisol 4.3 μg/dL, 60 min 6.1 μg/dL, expected > 18). There was no history of recent or extended treatment with exogenous glucocorticoids. EPP may result from incomplete inferior extension of the diencephalon during embryologic development or occur after events such as pituitary surgery or severe head injury that result in transection of the pituitary stalk. Mutations in multiple genes involved in neuronal migration and pituitary development, including HESX1, GLI2, and PROP1, have been identified in congenital cases of EPP. Anterior pituitary deficits were identified in over 80% of patients in one pediatric series of EPP patients, with corticotroph axis deficiencies in approximately two-thirds of patients. Diabetes insipidus is uncommon and occurs in fewer than 10% of EPP cases. This patient’s case of EPP is highly unusual because it was diagnosed incidentally and well into adulthood. Remote head trauma may have been the inciting event for EPP to occur, though this cannot be confirmed. The diagnosis of isolated secondary adrenal insufficiency in this patient’s case illustrates the importance of screening anterior pituitary function in all patients with EPP.

A rare case of 46,XX gonadal dysgenesis, Mayer-Rokitansky-Kuster-Hauser syndrome, pituitary and thyroid hypoplasia.

SummaryMayer–Rokitansky–Kuster–Hauser syndrome is characterized by congenital absence or hypoplasia of the uterus and upper two-thirds of the vagina in both phenotypically and karyotypically normal females with functional ovaries, whereas gonadal dysgenesis is a primary ovarian defect in otherwise normal 46,XX females. An association between these two conditions is extremely rare. We report a 21-year-old female presented with primary amenorrhea and undeveloped secondary sexual characteristics. The karyotype was 46,XX and the hormonal profile revealed hypothyroidism and hypogonadotropic hypogonadism. Pelvic MRI showed class I Mullerian duct anomaly with ovarian dysgenesis. Ultrasound showed bilateral thyroid hypoplasia and brain MRI suggested anterior pituitary hypoplasia. Levothyroxine and hormone replacement therapy were started.Learning pointsThe simultaneous presentation of 46,XX gonadal dysgenesis, Mayer–Rokitansky–Kuster–Hauser syndrome, hypothyroidism, and pituitary hypoplasia is a Possibility.Extensive evaluation should be made when a patient presents with one or more of these features.The diagnosis imposes a significant psychological burden on patients and adequate counseling should be provided.Hormone replacement therapy remains the only therapeutic option for the development of secondary sexual characteristics and the prevention of osteoporosis.

Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency

PurposeWe aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. MethodsWe used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. ResultsWe described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke’s pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. ConclusionOur findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function.

Congenital hypopituitarism due to novel compound heterozygous POU1F1 gene mutation: A case report and review of the literature

Failure to thrive is one of the most common complaints in the endocrinology and genetics clinic. An 8-month-old girl with presentation of motor developmental delay, failure to thrive, and midline facial defects, with history of hypoglycemia at birth and central congenital hypothyroidism (CCH), was brought to our genetic clinic. Hormone test demonstrated combined pituitary hormone deficiency with growth hormone deficiency (GHD), central hypothyroidism, and hypoprolactinemia. Brain magnetic resonance imaging (MRI) showed anterior pituitary hypoplasia (APH), abnormal pituitary stalk, and preserved posterior pituitary lobe. Whole exome sequence (WES) identified a compound heterozygous mutation of the POU1F1 gene: c.649C>T (p.Arg217Ter) and c.662T>C (p.Ile221Thr), which are de novo mutation and inherited from mother, respectively. The patient's phenotype was consistent clinically with congenital hypopituitarism due to the POU1F1 gene mutation. Based on our literature review, this is the first report of the c.662T>C mutation, to the best of our knowledge. Our study demonstrates the power of WES for early diagnosis of congenital hypopituitarism with its relative phenotype for improving prognosis and preventing irreversible deficit.

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.

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified seven variants, four of which putatively damaging, in FAT2 and DCHS2 in six patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency and two presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2-/- mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4-/- and Dchs1-/- mouse mutants but all animal models displayed normal commitment to the anterior pituitary cell type. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.

CDON gene contributes to pituitary stalk interruption syndrome associated with unilateral facial and abducens nerve palsy

The relationship between congenital defects of the brain and facial anomalies was proven. The Hedgehog signaling pathway plays a fundamental role in normal craniofacial development in humans. Mutations in the sonic hedgehog (SHH) signaling gene CDON have been recently reported in patients with holoprosencephaly and with pituitary stalk interruption syndrome (PSIS). This study’s aim was an elucidation of an 18-year-old patient presenting PSIS, multiple pituitary hormone deficiency, and congenital unilateral facial and abducens nerve palsy. Additionally, bilateral sensorineural hearing loss, dominating at the right site, was diagnosed. From the second year of life, growth deceleration was observed, and from the age of eight, anterior pituitary hormone deficiencies were gradually confirmed and substituted. At the MRI, characteristic triad for PSIS (anterior pituitary hypoplasia, interrupted pituitary stalk and ectopic posterior lobe) was diagnosed. We performed a comprehensive genomic screening, including microarrays for structural rearrangements and whole-exome sequencing for a monogenic defect. A novel heterozygous missense variant in the CDON gene (c.1814G > T; p.Gly605Val) was identified. The variant was inherited from the mother, who, besides short stature, did not show any disease symptoms. The variant was absent in control databases and 100 healthy subjects originating from the same population. We report a novel variant in the CDON gene associated with PSIS and congenital cranial nerve palsy. The variant revealed autosomal dominant inheritance with incomplete penetrance in concordance with previous studies reporting CDON defects.

Diagnosis of Childhood and Adolescent Growth Hormone Deficiency Using Transcriptomic Data

Background: We have shown that gene expression (GE) data have promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD)1. Our previous study compared GE data in children with GHD to healthy control children of normal stature. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group. Methods: GE data were obtained from patients undergoing growth hormone stimulation testing via a sample of blood taken at the start of the test. Arginine and glucagon stimulation tests with a cut-off for peak GH of <7mcg/L (IDS iSYS assay) were used for the diagnosis of GHD. GE was assessed in peripheral blood mononuclear cells via RNA-seq using the Illumina HiSeq 4000 platform. Data were taken for the 271 genes whose expression was utilised in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status. Boruta was used to assess which of the genes were contributing to the predictive capacity. Results: Twenty-four patients were recruited to the study, with eight subsequently diagnosed with GHD. Of the eight patients diagnosed with GHD, three had two stimulation tests and five had one stimulation test with anterior pituitary hypoplasia (in addition one patient had an arachnoid cyst and another a thin stalk). Median (range) peak GH was 2.5 (0.1 - 5) mcg/L in the GHD group and 11.0 (7.4 - 31) mcg/L in the non-GHD group.There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I or IGFBP-3 SDS) between the GHD and non-GHD subjects. 82 of the 271 genes used in our previous study were above the threshold of detection for RNA-seq in this study. A random forest algorithm using these 82 genes gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. Boruta was able to identify 65/82 genes with predictive capacity greater than permuted data within the dataset. Using a gene ontology approach the top fifty biological processes generated 16 clusters by affinity propagation which included regulation of TORC1 signalling and inositol phosphate metabolism. Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis and validates the findings of our original study. 1Murray etal (2018) JCI Insight 3(7): e93247

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.

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.

Pituitary stalk interruption syndrome is characterized by genetic heterogeneity.

Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist. Exome sequencing was performed in 52 (33 boys and 19 girls), including 2 familial cases single center pediatric cases, among them associated 36 (69.2%) had associated symptoms or syndromes. We identified rare and novel variants in genes (37 families with 39 individuals) known to be involved in one or more of the following—midline development and/or pituitary development or function (BMP4, CDON, GLI2, GLI3, HESX1, KIAA0556, LHX9, NKX2-1, PROP1, PTCH1, SHH, TBX19, TGIF1), syndromic and non-syndromic forms of hypogonadotropic hypogonadism (CCDC141, CHD7, FANCA, FANCC, FANCD2, FANCE, FANCG, IL17RD, KISS1R, NSMF, PMM2, SEMA3E, WDR11), syndromic forms of short stature (FGFR3, NBAS, PRMT7, RAF1, SLX4, SMARCA2, SOX11), cerebellum atrophy with optic anomalies (DNMT1, NBAS), axonal migration (ROBO1, SLIT2), and agenesis of the corpus callosum (ARID1B, CC2D2A, CEP120, CSPP1, DHCR7, INPP5E, VPS13B, ZNF423). Pituitary stalk interruption syndrome is characterized by a complex genetic heterogeneity, that reflects a complex phenotypic heterogeneity. Seizures, intellectual disability, micropenis or cryptorchidism, seen at presentation are usually considered as secondary to the pituitary deficiencies. However, this study shows that they are due to specific gene mutations. PSIS should therefore be considered as part of the phenotypic spectrum of other known genetic syndromes rather than as specific clinical entity.

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development.

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency, and 2 presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2–/– mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4–/– and Dchs1–/– mouse mutants, but all animal models displayed normal commitment to anterior pituitary cell types. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.

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.

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.