Pituitary Gland Hypoplasia Research Articles

Isolated growth hormone deficiency and amenorrhea – Case report

Growth hormone (GH) deficiency is the most common hypopituitarism disorder. We highlight the challenges to its diagnosis and management in the setting of a developing country. A 14-year-old came with a chief complaint of inability to menstruate. Menarche was at 12-years old, lasted 7 days, soaking 2 pads/day which discontinued shortly after. Thelarche was at 12-years-old and her breast is at Tanner stage 3. Her axillary and pubic hair are at Tanner stage 1. Height was 120 cm, weight 34.8 kg, height for age z-score<-3. Her lab results were normal for estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin. Bone age was suitable for age. Magnetic resonance imaging revealed pituitary gland hypoplasia (5.3 mm). A hormonal panel 3 years prior showed abnormally low GH level but normal cortisol and thyroid hormone levels. She was diagnosed with isolated growth hormone deficiency (IGHD) with delayed puberty. She was treated with medroxyprogesterone tablets once daily, after which her menstruation restarted. However, due to her economic background, she declined genetic tests, discontinued her medication and amenorrhea recurred. Amenorrhea present after a brief menarche should alert gynaecologists of a possible multi-hormone disorder with an underlying structural abnormality. IGHD may be due to a structural abnormality, such as pituitary gland hypoplasia. Unfortunately, economic reasons prevented the patient from receiving optimal treatment. IGHD rarely presents with a gynaecological complaint. Hormonal and genetic tests along with imaging should be undertaken. Growth hormone supplementation is the treatment of choice.

Novel Variants and Phenotypes in NEUROG3-Associated Syndrome.

Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete. To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot. Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity. In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3. This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.

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.

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 caused by a novel FLNA splice site mutation: a case report

BackgroundSepto-optic dysplasia (SOD), also known as de-Morsier syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain including absence of the septum pellucidum and corpus callosum dysgenesis. The variable presentation of SOD includes visual, neurologic, and/or hypothalamic-pituitary endocrine defects. The unclear aetiology of a large proportion of SOD cases underscores the importance of identifying novel SOD-associated genes.Case presentationTo identify the disease-causing gene in a male infant with neonatal hypoglycaemia, dysmorphic features, and hypoplasia of the optic nerve and corpus callosum, we designed a targeted next-generation sequencing panel for brain morphogenesis defects. We identified a novel hemizygous deletion, c.6355 + 4_6355 + 5delAG, in intron 38 of the FLNA gene that the patient had inherited from his mother. cDNA studies showed that this variant results in the production of 3 aberrant FLNA transcripts, the most abundant of which results in retention of intron 38 of FLNA.ConclusionsWe report for the first time a case of early-onset SOD associated with a mutation in the FLNA gene. This finding broadens the spectrum of genetic causes of this rare disorder and expands the phenotypic spectrum of the FLNA gene.

New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review

BackgroundMutations occurring in the orthodenticle homeobox 2 gene (OTX2) are responsible for a rare genetic syndrome, characterized mainly by microphthalmia/anophthalmia associated with extra-ocular defects such as brain malformations, pituitary abnormalities, short stature and intellectual disability. To date, the spectrum of radiological features observed in patients with OTX2 mutations has never been summarized.Case presentationIn this report, we describe a case of large microdeletion encompassing OTX2 but not BMP4 presenting with a syndromic anophthalmia with corpus callosum hypoplasia, pituitary gland hypoplasia and vermian hypoplasia.ConclusionOur case report provides an illustration of the neuroradiological spectrum in a case of OTX2-related syndrome and the first radiological evidence of 14q22.2q23.1 deletion associated posterior cranial fossa anomalies.

Premature Expression of FOXO1 in Developing Mouse Pituitary Results in Anterior Lobe Hypoplasia.

The process by which the somatotrope lineage emerges in the developing pituitary is regulated by the activity of specific signaling and transcription factors expressed during development. We set out to understand the contribution of FOXO1 to that process by using a mouse model in which FOXO1 is prematurely expressed in the pituitary primordium. Expression of FOXO1 in the oral ectoderm as early as embryonic day (e)9.5 resulted in pituitary gland hypoplasia and reduced expression of anterior lobe hormone transcripts at e18.5. Of note, the relative numbers of somatotropes and thyrotropes were also decreased at e18.5. LHX3 and PITX2, markers of pituitary identity, were present in a reduced number of cells during the formation of the Rathke pouch. Thus, premature expression of FOXO1 may affect adoption of pituitary identity during differentiation. Our results demonstrate that the timing of FOXO1 activation affects its role in pituitary gland organogenesis and somatotrope differentiation.

A patient with pseudohypoaldosteronism type II complicated by congenital hypopituitarism carrying a KLHL3 mutation.

.Pseudohypoaldosteronism type II (PHA II) is a renal tubular disease that causes hyperkalemia, hypertension, and metabolic acidosis. Mutations in four genes (WNK4, WNK1, KLHL3, and CUL3) are known to cause PHA II. We report a patient with PHA II carrying a KLHL3 mutation, who also had congenital hypopituitarism. The patient, a 3-yr-old boy, experienced loss of consciousness at age 10 mo. He exhibited growth failure, hypertension, hyperkalemia, and metabolic acidosis. We diagnosed him as having PHA II because he had low plasma renin activity with normal plasma aldosterone level and a low transtubular potassium gradient. Further investigations revealed defective secretion of GH and gonadotropins and anterior pituitary gland hypoplasia. Genetic analyses revealed a previously known heterozygous KLHL3 mutation (p.Leu387Pro), but no mutation was detected in 27 genes associated with congenital hypopituitarism. He was treated with sodium restriction and recombinant human GH, which normalized growth velocity. This is the first report of a molecularly confirmed patient with PHA II complicated by congenital hypopituitarism. We speculate that both GH deficiency and metabolic acidosis contributed to growth failure. Endocrinological investigations will help to individualize the treatment of patients with PHA II presenting with growth failure.

Complex chromosomal rearrangements causing Langer–Giedion syndrome atypical phenotype: Genotype–phenotype correlation and literature review

Langer-Giedion syndrome (LGS) is caused by a deletion of chromosome 8q23.3-q24.11. The LGS clinical spectrum includes intellectual disability (ID), short stature, microcephaly, facial dysmorphisms, exostoses. We describe a 4-year-old girl with ID, short stature, microcephaly, distinctive facial phenotype, skeletal signs (exostoses on the left fibula, coccyx agenesis, stubby and dysmorphic sphenoid bone, osteoporosis), central nervous system malformations (hypoplastic and dysmorphic corpus callosum and septum pellucidum), pituitary gland hypoplasia and hyperreninemia. Array-CGH revealed complex chromosomal rearrangements. A diagnosis of LGS was confirmed by the detection of a 8q23.3-q24.1 deletion. Associated chromosomal abnormalities were a 21q22.1 deletion and a balanced reciprocal translocation t(2;11)(p24;p15) de novo, confirmed by FISH analysis. We document the patient's atypical findings, never described in LGS patients, in order to update the genotype-phenotype correlation. We speculate that the disruption of regulatory elements mapping upstream CYP11B2 involved in the deleted region could cause hyperreninemia.

Septo-optic dysplasia complex: Clinical and radiological manifestations in Omani children

Background:Septo-optic dysplasia (SOD), also known as de-Morsier's syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia (ONH), pituitary gland hypoplasia, and midline abnormalities of the brain including absence of septum pellucidum and corpus callosum dysgenesis. It is typically diagnosed in infancy and has a variable presentation that includes visual, neurologic, and/or hypothalamic-pituitary endocrine deficits.Purpose:To demonstrate the ophthalmic, endocrine, and neurologic spectrum of SOD in five Omani children and address the crucial role of high-resolution neuroimaging for its early and accurate diagnosis.Materials and Methods:A retrospective chart review was performed in 2010 of all children in the pediatric ophthalmology database of Sultan Qaboos University Hospital (SQUH) who were diagnosed to have ONH. All relevantdemographic, ophthalmic, neurologic, endocrine, and neuro-radiological manifestations were recorded in a data collection form. All previous neuroimaging results were reviewed by a neuro-radiologist.Results:Five patients (four males, one female) with the diagnosis of ONH were included in the study. They presented during the period 1998-2008. All patients were born at term, with normal birth weights to healthy mothers with insignificant antenatal history. Age at presentation ranged from three months to one year. Manifestations at presentation included severe visual impairment (5/5), neonatal hypoglycemia (3/5), seizure disorder (2/5), and failure to thrive (4/5). ONH was bilateral in 3/5 patients and unilateral in (2/5). Brain and orbit imaging revealed varying anomalies in all patients. These included absent septum pellucidum (3/5), severe corpus callosum agenesis (1/5), ectopic pituitary (5/5), falx cerebri deficiency (1/5), optic nerve hypoplasia (5/5), optic chiasmal hypoplasia (5/5), and olfactory tract hypoplasia (1/5). Endocrine deficits were detected in 4/5 patients (3 with panhypopituitarism, and 1 with growth hormone deficiency) and necessitated replacement therapy.Conclusion:SOD is a clinically heterogeneous disorder with a wide spectrum of ophthalmic, endocrine, and neurologic manifestations. All features might not be present in a single patient. A high consanguinity rate and lack of history of alcohol and drug use were observed in our cohort. Most affected children present first to the pediatrician with failure to thrive. Radiological confirmation of ONH necessitates high-resolution imaging and interpretation by an experienced neuro-radiologist. In our cohort, all patients with ONH had associated optic chiasmal hypoplasia. Early detection and treatment reduces disease-related morbidity, and can be life saving.

Évaluation de la prise en charge de patients présentant un déficit en hormone de croissance (GHD) traité dans l’enfance, avant et après la période de la transition

Growth hormone deficiency (GHD) may result from a failure of hypothalamic GHRH production or release, from congenital disorders of pituitary development, or from central nervous system insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases. Idiopathic, isolated GHD is the most common sporadic form of hypopituitarism. GHD may also occur in combination with other pituitary hormone deficiencies, and is often referred to as hypopituitarism, combined pituitary hormone deficiency (CPHD), multiple pituitary hormone deficiency (MPHD) or panhypopituitarism. Children without any identifiable cause of their GHD are commonly labeled as having idiopathic hypopituitarism.MRI imaging is the technique of choice in the diagnosis of children with hypopituitarism. Marked differences in MRI pituitary gland morphology suggest different etiologies of GHD and different prognoses. Pituitary stalk agenesis and ectopic posterior pituitary (EPP) are specific markers of permanent GHD, and patients with these MRI findings show a different clinical and endocrine outcome compared to those with normal pituitary anatomy or hypoplastic pituitary alone. Furthermore, the classic triad of ectopic posterior pituitary gland, pituitary stalk hypoplasia/agenesis, and anterior pituitary gland hypoplasia is generally associated with permanent GHD. T2 DRIVE images aid in the identification of pituitary stalk without the use of contrast medium administration. Future developments in imaging techniques will undoubtedly reveal additional insights. Mutations in a number of genes encoding transcription factors – such as HESX1, SOX2, SOX3, LHX3, LHX4, PROP1, POU1F1, PITX, GLI3, GLI2, OTX2, ARNT2, IGSF1, FGF8, FGFR1, PROKR2, PROK2, CHD7, WDR11, NFKB2, PAX6, TCF7L1, IFT72, GPR161 and CDON – have been associated with pituitary dysfunction and abnormal pituitary gland development; the correlation of genetic mutations to endocrine and MRI phenotypes has improved our knowledge of pituitary development and management of patients with hypopituitarism, both in terms of possible genetic counseling, and of early diagnosis of evolving anterior pituitary hormone deficiencies.

Index of Suspicion * Case 1: Leg Cramps, Hand Spasms, Diarrhea, and Substantial Weight Loss in a 12 Year Old * Case 2: Hypothermia, Hypoglycemia, and Hyperbilirubinemia in a Neonate * Case 3: Recurrent Fevers, Abdominal Pain, and Cervical Lymphadenopathy in a 7 Year Old

A 12-year-old previously healthy boy presents with leg cramps for 2 weeks and spasms of his hands since yesterday. He also complains of nausea, bloating, epigastric pain, and recurrent watery and loose stools for 1 month. Currently, he is taking lansoprazole for epigastric pain without any relief. He also has a history of involuntary weight loss of 10 lb over 2 months. The family history contains no findings of note. On physical examination, the boy's weight is 36 kg (25th percentile) and height is 140 cm (10th percentile) and he exhibits a positive Trousseau sign and negative Chvostek sign. Remaining physical signs, including on abdominal examination, are normal. Laboratory evaluation shows hypocalcemia (total calcium of 5.3 mg/dL [1.3 mmol/L], ionized calcium of 2 mg/dL [0.5 mmol/L], and corrected calcium of 6.1 mg/dL [1.5 mmol/L]) as well as hypoalbuminemia (3 g/dL [30 g/L]). Serum magnesium measures 1.6 g/dL. CBC shows Hgb of 9.3 g/dL (93 g/L), Hct of 29% (0.29), WBC count of 9.9×103/μL (9.9×109/L), platelet count of 471×103/μL (471×109/L), mean corpuscular volume of 67 fL, and reticulocyte count of 1% (0.01). Results of the iron studies are consistent with iron deficiency anemia, with a serum iron concentration of 6 μg/dL (1.07 μmol/L) (31 to 144 μg/dL [5.5 to 25.8 μmol/L]), transferrin saturation of 3% (0.3), and serum ferritin less than 5 ng/mL (11.23 pmol/L) (21 to 275 ng/mL [47.2 to 617.9 pmol/L]). ESR is 46 mm/h and CRP is 9.5 mg/dL (normal <0.05 mg/dL). His serum 25-hydroxyvitamin D concentration is low at 5.7 ng/mL (14.2 nmol/L) (normal, 32 to 100 ng/mL [79.9 to 249.6 nmol/L]) and serum parathyroid hormone, urine calcium, and creatinine values are within normal limits. His tetany and hypocalcemia resolve with calcium replacement. Additional evaluation leads to the diagnosis. …

Deletion at 14q22‐23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies

Anophthalmia and pituitary gland hypoplasia are both debilitating conditions where the underlying genetic defect is unknown in the majority of cases. We identified a patient with bilateral anophthalmia and absence of the optic nerves, chiasm and tracts, as well as pituitary gland hypoplasia and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28;q23.2). Translocation breakpoint analysis using FISH and high-resolution microarray comparative genomic hybridization (CGH) has identified a 9.66 Mb deleted region on the long arm of chromosome 14 which includes the genes BMP4, OTX2, RTN1, SIX6, SIX1, and SIX4. Three other patients with interstitial deletions involving 14q22-23 have been described, all with bilateral anophthalmia, pituitary abnormalities, ear anomalies, and a facial phenotype similar to our patient. OTX2 is involved in ocular developmental defects, and the severity of the ocular phenotype in our patient and the other 14q22-23 deletion patients, suggests this genomic region harbors other gene/s involved in ocular development. BMP4 haploinsufficiency is predicted to contribute to the ocular phenotype on the basis of its expression pattern and observed murine mutant phenotypes. In addition, deletion of BMP4 and SIX6 is likely to contribute to the abnormal pituitary development, and SIX1 deletion may contribute to the ear and other craniofacial features. This indicates that contiguous gene deletion may contribute to the phenotypic features in the 14q22-23 deletion patients.

The impact of R53C mutation on the three-dimensional structure, stability, and DNA-binding properties of the human Hesx-1 homeodomain.

Septo-optic dysplasia (SOD) is loosely defined as any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain. Recent studies have shown that this rare disease has its origin in key mutations in Hesx-1, a protein that plays a critical role in normal development of the forebrain, eyes, and other anterior structures during embryogenesis. R53C mutation in the Hesx-1 homeodomain has recently been identified in some patients with SOD. However, no detailed description of the effect of this mutation on the protein structure, stability, and function has been reported so far. The impact of R53C substitution on Hesx-1 homeodomain structure, stability, and DNA-binding properties was analyzed by using a combination of NMR spectroscopy, molecular modeling and circular dichroism experiments. Although R53C mutation has very slight effects on protein structure, it has a profound impact on homeodomain stability. We show that intramolecular disulfide formation can be easily accomplished in the mutated homeodomain, which suggests that such bond formation could take place in vivo. This modification has a key effect on the homeodomain structure and stability, mainly through its effect on helix I/helix III packing. Finally, CD titrations allowed us to establish the energy cost of the R53C substitution with respect to Hesx-1-homeodomain-DNA complex stability. Detailed structural models are provided for the wild-type human Hesx-1 homeodomain and the R53C mutant, which is associated with SOD in humans. The reported effect of R53C mutation on protein stability and DNA-binding properties, together with the significant structural perturbations induced by disulfide formation in the mutated polypeptide might explain the loss of activity of the mutant in vivo.