Ectopic Posterior Lobe Research Articles

8380 Pituitary Stalk Interruption Syndrome, A Rare Cause of Panhypopituitarism

Abstract Disclosure: F. Abdulkarim: None. E. Alshdifat: None. P. Henriquez Feliz: None. J. Vargas-Jerez: None. T. Zahra: None. Pituitary Stalk Interruption Syndrome, A Rare Cause of Panhypopituitarism Faridat Abdulkarim, MD. Esra’a Alshdifat, MD. Pamela Henriquez Feliz, MD. Julia Vargas- Jerez, MD. and Tasneem Zahra, MD. Introduction: Pituitary stalk interruption syndrome (PSIS) is a rare congenital pituitary anatomical abnormality with reported incidence of 0.5 per 100,000 live births. It is characterized by the triad of thin or interrupted pituitary stalk, absent or ectopic posterior lobe and hypoplastic or aplastic anterior lobe seen on MRI. The anterior pituitary function is usually impaired however the posterior pituitary is usually intact and normal. We report a case of a Now 34-year-old Female who presented to the endocrine clinic with underdeveloped sexual characteristics. MRI done was consistent with PSIS. This is the second case of PSIS we report from our Institution. Case Presentation: A Now 34-year -old Hispanic American Female presented to our endocrine clinic with underdeveloped secondary sexual characteristics. She had panhypopituitarism, including Growth hormone deficiency and was treated with growth hormone from early childhood until age 13-14 years. She re-presented to our clinic at the age of 28 years after being lost to follow up for many years. On physical examination, she was 175cm tall, weighed 89.4kg and BMI 29.1kg/m2Patient has pre-pubertal breast, tanner stage 1, no axillary hair, small external genitalia with scanty pubic hair. Hormonal analysis revealed Estradiol <5 pg/mL (low), FSH 0.4 IU/L (low), LH <0.3 IU/L (low), Progesterone 0.1ng/mL (Low), Testosterone <2.5 ng/dL (8.4- 48.1ng/dl) Prolactin 22.3ng/mL (3.4-24.1 ng/ml), TSH 0.88uIU/mL (0.27-4.20), Free T4 0.5ng/dl (0.9-1.8) , ACTH 7.7pg/mL (7.2-63.3), Baseline AM Cortisol 0.7ug/dL (6.0-18.4) and 5.5 ug/dL after Cosyntropin test, IGF-1 17ng/mL (83-280). Urinalysis revealed normal specific gravity. Chromosome analysis with Normal Karyotype 46XX. Pelvic US revealed Markedly diminutive uterus and ovaries. MRI of the pituitary was highly suggestive of PSIS. She is currently being treated with levothyroxine and hydrocortisone Conclusion: PSIS is a rare congenital abnormality. Fortunately has good prognosis, however if left undiagnosed/untreated has high mortality mainly from Adrenal insufficiency and Myxedema coma. The patient discussed above, has underdeveloped sexual characteristics and primary amenorrheaLaboratory finding consistent with Panhypopituitarism with Normal prolactin which is the case in most patient with PSIS. Imaging revealed atrophic uterus and ovaries, and MRI revealed Findings which are highly suggestive of PSISShe previously had problems with outpatient clinic visits and medication compliance. However, she is currently compliant with hormonal replacement therapy which is the mainstay of treatment. Presentation: 6/3/2024

Pituitary Stalk Interruption Syndrome in a Child: A Rare Case Report with Literature Review

Introduction Pituitary stalk interruption syndrome is an exceedingly rare congenital abnormality affecting the pituitary gland that is still not fully understood. This study presents a 7-year-old child with the disease. Case presentation A 7-year-old male child was presented with short stature, school performance postponement, and an intellectual disability at a mild level. At 6.5 years of age, he had no facial features, was wearing eyeglasses, and had a weight and height of 20 kg (25th percentile) and 101 cm (3rd percentile), respectively. At the age of 7 years, his height was 117 cm (10th percentile) and his weight was 25 kg (50th percentile). Most laboratory tests were normal. However, insulin-like growth factor-1 and glucagon levels were low. A dynamic magnetic resonance imaging of the pituitary gland revealed an ectopic posterior pituitary lobe and the absence of a pituitary stalk. The patient was put on hormone replacement therapy (Norditropin pen) to control the growth hormone deficiency, and he was put under a close follow-up to monitor growth and panhypopituitarism. Conclusion Although hormone replacement therapy is associated with satisfactory outcomes in treating the syndrome, lifelong follow-up is indicated as new hormone deficiencies may arise later in life.

Abstract #1323828: Pituitary Stalk Interruption Syndrome Presentation at Adult Age

Pituitary stalk interruption syndrome (PSIS) is a rare congenital abnormality of the pituitary gland, a multigenic condition with phenotypic variability that could be due to a genetic mutation during embryogenesis in PROP1, LHX3, HEXSX1, PROKR2, and GPR161 or due to birth asphyxia. Diagnosis is made radiologically with the triad of an interrupted pituitary stalk, hypoplastic anterior lobe, and an ectopic posterior lobe. The prevalence is estimated to be 0.5 in 1,000,000 patients. In another study involving 231 adult patients with hypopituitarism, 11.2% had PSIS.

Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum.

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

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.

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

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

SAT-LB58 Molecular Investigation of Recessive Inheritance by Exome Sequencing of Patients With Congenital Hypopituitarism

Background: Growth hormone deficiency (GHD) occurs in ~ 1/8000 individuals, and 14% of the patients have mutations in five major candidate genes. However, over 30 genes have been implicated in hypopituitarism. WES (Whole Exome Sequencing) is a promising approach for molecular diagnosis of patients with GHD because it offers the opportunity to screen for all known genes in addition to novel disease gene discovery. Methods: WES was performed for 13 unrelated patients with congenital hypopituitarism born from consanguineous parents. The variants were filtered assuming autosomal recessive inheritance, rare variants in population databases, in silico analysis predicted as deleterious and pituitary and/or hypothalamus gene expression. To determine whether variants in CDH2 that were predicted to be deleterious were functionally significant, L1 fibroblast lines that have no endogenous CDH2 protein were stably transfected with either human wild type or variant CDH2, the transfected cells were labelled with lipophilic dyes, and cell adhesion properties were assessed. Results: Homozygous pathogenic or likely pathogenic allelic variants were found in 2 of the 13 patients. First, a female patient with GH, TSH, ACTH and LH/ FSH deficiencies presenting ectopic posterior pituitary lobe, non-visualized stalk, and hypoplastic anterior pituitary lobe had two homozygous rare variants predicted as deleterious: PLA2G4A p.Asn703Lys and CDH2 c.865G>A (p.Val289Ile). Only CDH2 is known to be expressed in the pituitary, and Pla2g4a null mice have a pleiotropic phenotype without obvious hypopituitarism. The CDH2 variant is rare and classified as deleterious. Sanger sequencing of CDH2 in four family members of the affected proband revealed that the unaffected parents and two unaffected siblings were heterozygous carriers. The effect of the CDH2 variant on cell aggregation was assessed in cell culture. Large cell aggregates formed in cells transfected with wild type CDH2, but cell aggregates were small or absent in cells that were either non-transfected or transfected with the CDH2 variant. Second, a patient with isolated GHD and no MRI abnormalities was identified with a rare, likely deleterious, homozygous GH1 c.171delT (p. Phe 57Leufs*43) variant. He had a sister who died at the age of 5 and had features of GHD. Conclusion: In a cohort of congenital hypopituitarism from consanguineous parents we had 15% molecular diagnosis using WES. We identified a variant in a known gene, GH1 c.171delT and a variant in a novel gene, CDH2 p.Val289I.

Central Diabetes Insipidus in an Extremely-Low-Birth-Weight Preterm Infant with Suspected Ectopic Posterior Lobe of the Pituitary Gland

Central Diabetes Insipidus in an Extremely-Low-Birth-Weight Preterm Infant with Suspected Ectopic Posterior Lobe of the Pituitary Gland

Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients.

Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

A case of an infant with congenital combined pituitary hormone deficiency and normalized liver histology of infantile cholestasis after hormone replacement therapy.

.Congenital combined pituitary hormone deficiency (CPHD) may present with cholestasis in the neonate or during early infancy. However, its precise mechanism is unknown. A 3-mo-old boy presented with cryptorchidism and hypoplastic scrotum after birth. Neonatal jaundice was noted but temporarily improved with phototherapy. Jaundice recurred at 2 mo of age. Elevated direct bilirubin (D-Bil) and liver dysfunction were found but cholangiography showed no signs of biliary atresia (BA). Liver biopsy findings showed giant cell formation of hepatocytes with hypoplastic bile ducts. Subsequent magnetic resonance imaging (MRI) of the head revealed a hypoplastic pituitary gland with an ectopic posterior lobe, and the patient was diagnosed with congenital CPHD based on decreased secretion of cortisol and GH by the pituitary anterior lobe load test. D-Bil levels promptly improved after hydrocortisone (HDC) replacement. We subsequently began replacement with levothyroxine (L-T4) and GH, and liver histology showed normal interlobular bile ducts at 8 mo old. This is the first case report of proven histological improvement after hormone replacement therapy. This suggested that pituitary-mediated hormones, especially cortisol, might be involved in the development of the bile ducts.

Role of GLI2 in hypopituitarism phenotype.

GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was ≥ 0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.

Relatively high frequency of non‐synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly

GLI2 is a downstream transcription factor in Sonic Hedgehog signalling, acting early in ventral forebrain and pituitary development. Heterozygous nonsense GLI2 mutations have been reported in patients with isolated or combined pituitary hormone deficiency (CPHD), with or without holoprosencephaly. The aim of this study was to screen for GLI2 mutations in a large cohort of patients with congenital GH deficiency. The GLI2 coding region of 41 patients with severe isolated GH deficiency (IGHD) and 136 patients with CPHD was amplified by PCR using intronic primers and sequenced. The frequency of GLI2 variants was verified in up to 155 Brazilian controls and in the 1000 Genomes database. The consequences of allelic variants were analysed by the Polyphen, SIFT, Mutationtaster and SNAP prediction sites. Eighteen different heterozygous non-synonymous GLI2 variants were identified in 24 patients. Twenty-three patients had CPHD and one had IGHD. Two patients had additional diabetes insipidus, indicating deficiencies of anterior and posterior pituitary lobes. The posterior pituitary lobe on MRI was ectopic in 16, not visible in 4, normally placed in 2 and imaging was not available in two patients, but there were no signs of holoprosencephaly. Sixteen GLI2 variants were considered deleterious in at least one of the prediction sites. A relatively high frequency of non-synonymous GLI2 variants was identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with CPHD and an ectopic posterior pituitary lobe. In vitro functional assays may contribute to ascertain the deleterious consequences of these variants.

Novel Heterozygous Nonsense GLI2 Mutations in Patients with Hypopituitarism and Ectopic Posterior Pituitary Lobe without Holoprosencephaly

GLI2 is a transcription factor downstream in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. GLI2 mutations were reported in patients with holoprosencephaly (HPE) and pituitary abnormalities. The aim was to report three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families. The study was conducted at a university hospital. The GLI2 coding region of patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency was amplified by PCR using intronic primers and sequenced. Three novel heterozygous GLI2 mutations were identified: c.2362_2368del p.L788fsX794 (family 1), c.2081_2084del p.L694fsX722 (family 2), and c.1138 G>T p.E380X (family 3). All predict a truncated protein with loss of the C-terminal activator domain. The index case of family 1 had polydactyly, hypoglycemia, and seizures, and GH, TSH, prolactin, ACTH, LH, and FSH deficiencies. Her mother and seven relatives harboring the same mutation had polydactyly, including two uncles with IGHD and one cousin with GH, TSH, LH, and FSH deficiencies. In family 2, a boy had cryptorchidism, cleft lip and palate, and GH deficiency. In family 3, a girl had hypoglycemia, seizures, excessive thirst and polyuria, and GH, ACTH, TSH, and antidiuretic hormone deficiencies. Magnetic resonance imaging of four patients with GLI2 mutations and hypopituitarism showed a hypoplastic anterior pituitary and an ectopic posterior pituitary lobe without HPE. We describe three novel heterozygous frameshift or nonsense GLI2 mutations, predicting truncated proteins lacking the activator domain, associated with IGHD or combined pituitary hormone deficiency and ectopic posterior pituitary lobe without HPE. These phenotypes support partial penetrance, variable polydactyly, midline facial defects, and pituitary hormone deficiencies, including diabetes insipidus, conferred by heterozygous frameshift or nonsense GLI2 mutations.

A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency

Heterozygous mutations of the gene encoding transcription factor OTX2 were recently shown to be responsible for ocular as well as pituitary abnormalities. Here, we describe a patient with unilateral anophthalmia and short stature. Endocrine evaluation of the hypothalamic-pituitary axis revealed isolated growth hormone deficiency (IGHD) with small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and right anophthalmia on brain magnetic resonance imaging. DNA was analyzed for mutations in the HESX1, SOX2, and OTX2 genes. Molecular analysis yielded a novel heterozygous OTX2 mutation (c.270A>T, p.R90S) within the homeodomain. Functional analysis revealed that the mutation inhibited both the DNA binding and transactivation activities of the protein. This novel loss-of-function mutation is associated with anophthalmia and IGHD in a patient of Sephardic Jewish descent. We recommend that patients with GH deficiency and ocular malformation in whom genetic analysis for classic transcription factor genes (PROP1, POU1F1, HESX1, and LHX4) failed to identify alterations should be checked for the presence of mutations in the OTX2 gene.

Inicio tardío de hipopituitarismo debido a hipoplasia adenohipofisaria y ausencia de tallo con neurohipófisis ectópica en un paciente de 67 años de edad

Congenital hypopituitarism due to pituitary stalk and anterior pituitary hypoplasia accompanied by an ectopic posterior pituitary lobe is a rare disorder causing multiple hormone deficiencies. Clinical signs can be present at birth (hypoglycemia, prolonged jaundice and micropenis) and there can be severe growth restriction. Therefore, diagnosis is usually performed in childhood. We present the uncommon case of a 67-year-old man with hypopituitarism due to hypoplasia of the anterior pituitary and pituitary stalk together with an ectopic posterior pituitary who presented symptoms of hyponatremia due to adrenocorticotropic hormone deficiency.

OTX2 Loss of Function Mutation Causes Anophthalmia and Combined Pituitary Hormone Deficiency with a Small Anterior and Ectopic Posterior Pituitary

Orthodenticle homeobox 2 (OTX2) is a transcription factor necessary for ocular and forebrain development. In humans, heterozygous mutations of OTX2 cause severe ocular malformations. However, whether mutations of OTX2 cause pituitary structural abnormalities or combined pituitary hormone deficiency (CPHD) has not been clarified. We surveyed the functional consequences of a novel OTX2 mutation that was detected in a patient with anophthalmia and CPHD. We examined a Japanese patient with growth disturbance, anophthalamia, and severe developmental delay. He showed deficiencies in GH, TSH, LH, FSH, and ACTH. Brain magnetic resonance imaging revealed a small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and Chiari malformation. Sequence analysis of OTX2 demonstrated a heterozygous two bases insertion [S136fsX178 (c.576-577insCT)] in exon 3. The mutant Otx2 protein localized to the nucleus, but did not activate the promoter of the HESX1 and POU1F1 gene, indicating a loss of function mutation. No dominant negative effect in the presence of wild-type Otx2 was observed. This case indicates that the OTX2 mutation is a cause of CPHD. Further study of more patients with OTX2 defects is necessary to clarify the clinical phenotypes and endocrine defects caused by OTX2 mutations.

Laterality disturbance and hypopituitarism. A case report of co-existing situs inversus totalis and combined pituitary hormone deficiency

The authors present the case history of a 52-yr-old male patient with a unique association of combined pituitary hormone deficiency (CPHD) and situs inversus totalis. Except for signs and symptoms of pituitary hormone deficiency, the patient had no dysmorphic features, and hearing impairment, primary mental or neurological defects were also absent. Pituitary magnetic resonance imaging (MRI) scan showed hypoplasia of the anterior lobe of the pituitary gland and an ectopic posterior pituitary lobe. Despite the presence of situs inversus totalis, the patient was right-handed and functional MRI demonstrated left-hemisphere activation during language tests. Kartagener syndrome was considered, but immunofluorescence analysis showed normal localization of the outer dynein arm protein in respiratory epithelial cells obtained from the nasal mucosa. Direct DNA sequencing of all coding exons of the pituitary transcription factor 1 (PIT1) and prophet of PIT1 (PROP1) genes failed to detect disease-causing mutations, suggesting that these genes were not involved in the development of CPHD in our patient. More interestingly, the potential role of the paired like homeodomain transcription factor 2 (PITX2) gene, which has been implicated not only in CPHD, but also in left-right patterning in animal models, was also excluded, as sequencing showed the absence of mutations in coding exons of this gene. To our knowledge, PITX2 gene mutations have not been investigated in CPHD patients who had situs inversus totalis. We conclude that in contrast to animal models, the PITX2 gene is not involved in the development of situs inversus totalis, at least not in our CPHD patient.

A Novel Missense Mutation (P366T) of the LHX4 Gene Causes Severe Combined Pituitary Hormone Deficiency with Pituitary Hypoplasia, Ectopic Posterior Lobe and a Poorly Developed Sella Turcica

LIM homeodomain transcription factors regulate many aspects of development in multicellular organisms. LHX4/Lhx4 is a protein that is essential for pituitary development and motor neuron specification in mammals. In human, a heterozygous splicing mutation of the LHX4 gene was reported in a family with combined pituitary hormone deficiencies (CPHD). In addition to CPHD, these patients were characterized by small sella turcica and chiari malformation. Here we report a Japanese patient with CPHD (GH, PRL, TSH, LH, FSH, and ACTH deficiency) due to a novel missense mutation (P366T) of the LHX 4 gene. She showed severe respiratory disease and hypoglycemia soon after birth. Brain MRI demonstrated hypoplastic anterior pituitary, ectopic posterior lobe, a poorly developed sella turcica, and chiari malformation. Sequence analysis of the LHX 4 gene identified a heterozygous missense mutation (P366T) in exon 6, which was present in LIM4 specific domain. Neither of the patient's parents harbored this mutation, indicating de novo mutation.

Hormonal, pituitary magnetic resonance, LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe

LHX4 and HESX1 are important in early stages of pituitary development and their mutations can be associated with an ectopic posterior lobe (EPL) in the pituitary of patients with hypopituitarism. The EPL can be located at the median eminence or at the path of the pituitary stalk. The aim of this study was to analyse LHX4 and HESX1 and characterize the hormonal deficiency profiles, establishing relationships with magnetic resonance imaging (MRI) findings in these patients. Sixty-two patients with hypopituitarism associated with EPL were submitted to evaluation of pituitary function, analysis of MRI with EPL location and molecular analysis of LHX4 and HESX1 using polymerase chain reaction (PCR), digestion with restriction enzyme and automatic sequencing. Forty-two patients had a nonvisualized pituitary stalk (NPS), and 20 a visualized pituitary stalk (VPS). Most patients (95%) with NPS had combined pituitary hormone deficiency (CPHD), with ACTH deficiency in 85%. In patients with VPS, CPHD was found in 50% and ACTH deficiency occurred in only 20%. The frequency of the location of EPL was similar in patients with VPS and NPS: 35% at median eminence and 65% at the path of the stalk. No mutations in LHX4 and HESX1 were identified. Three new polymorphisms in LHX4 were found. ACTH deficiency is frequent in patients with hypopituitarism and NPS (85%), the location of EPL at the median eminence was not predictive of the hormonal profile [isolated GH deficiency (IGHD) or CPHD], and LHX4 and HESX1 genes mutations remain rare causes of hypopituitarism associated with EPL.

Untreated Hypopituitarism Due to Absence of the Pituitary Stalk with Normal Adult Height: Report of Two Cases

Patients with congenital multiple pituitary hormones deficiency (MPHD) occasionally present with pituitary stalk interruption and ectopic posterior lobe on magnetic resonance imaging (MRI). Very rarely normal adult height despite growth hormone deficiency (GHD) has been described in these patients. We report two patients with evidence of congenital MPHD, who remained untreated until adulthood. They both failed to develop spontaneous puberty, and they demonstrated very low growth velocity until adulthood when they continued to grow, with a final height of 176 and 169 cm when they sought medical attention in our department at the age of 45 and 33 yr, respectively. At that time a hypoplastic pituitary, absence of pituitary stalk, and ectopic posterior pituitary lobe were found on MRI, and the laboratory investigations, including dynamic tests for pituitary hormone reserve, revealed MPHD with severe GHD. In conclusion, these cases illustrate that very rarely patients with untreated MPHD can reach normal adult height. Some postulations about the pathophysiology of this phenomenon are discussed.