Small Anterior Pituitary Gland Research Articles

Abstract #1413009: Post Snake Bite Panhypopituitarism – Delay in Diagnosis or Delayed Presentation

Panhypopituitarism is a condition of inadequate or absent production of the anterior pituitary hormones. Simmonds’ disease was first described in 1914 by the German pathologist Simmond. Post snake bite panhypopituitarism is a described entity. Hypopituitarism following Russell’s viper bite was first reported in 1976 by Eapen et al in three adults from Kerala in South India. Most of the cases are diagnosed long after the snake bite, and this delay has been attributed to clinical inertia and lack of awareness. But on careful analysis of the case reports, it is found that at least a few of them started having symptoms after a latent period, which can be up to 5 years. We present 7 cases of post snakebite hypopituitarism, which were diagnosed late, but also had a delayed onset of symptoms. 7 patients, who were diagnosed to have post snake bite hypopituitarism between May 2020 and May 2022 were studied. All patients were male. The type of snake, the complications and treatment initially given were studied, and then the time of onset of symptoms of hormonal deficiencies was collected. All patients underwent relevant hormonal tests, including dynamic tests and imaging for pituitary. All patients were male, all were bitten by Russels viper, all had hypotension after the bite and required blood transfusions and hemodialysis. The mean duration from the snake bite to the diagnosis was 7.75 years. The onset of symptoms was also delayed, with symptoms occurring an average 4.25 years after the snake bite. All patients had symptoms of hypogonadism, which was the first symptom to occur in 5 out of 7 patients. Lethargy, tiredness, weakness were present in all and appeared next, a mean of 6 months later. Symptoms of adrenal insufficiency appeared in all patients, a mean of 2.5 years later. Adrenal crisis occurred in patients, a mean of 13 months later. On hormonal evaluation all patients had panhypopituitarism, (low FSH/LH Testosterone, Cortisol, IGF1, and FT4). MRI done showed empty sella in 5 patients and small anterior pituitary in 2 patients. Hypopituitarism is an important sequel of Russell’s viper bite in South India. A high degree of suspicion is needed to diagnose this condition following Russell’s viper bite. Contrary to our earlier understanding of post snake bite hypopituitarism, the pituitary damage is not a single time event, but a gradual loss of pituitary function initiated by the snake bite, which results in a delayed appearance of symptoms. The sequence of loss of pituitary hormone functions- Gonadotropin- GH-Thyrotropin-ACTH also points to the same fact. The possible explanation is drawn from the analogy of Sheehan’s syndrome presenting late, where the late presentation is due to an autoimmune destruction, initiated by the snake bite (Anti pituitary antibody positive). The delay in diagnosis is at least contributed by the late appearance of panhypopituitarism, and the diagnosis should be considered in all patients with significant viper bite, presenting with symptoms suggestive of panhypopituitarism, however late may the onset of symptoms be.

Pituitary stalk transection syndrome

Growth hormone deficiency is one of the most common endocrinological causes for short stature. It can either be idiopathic or associated with organic causes like tumors or following surgery. One of the rare causes for growth hormone deficiency in children is pituitary stalk transection syndrome. It can be diagnosed by magnetic resonance imaging of the hypothalamus and pituitary gland which shows an ectopic or absent posterior pituitary, an absent or interrupted pituitary stalk, or small anterior pituitary in combination with growth hormone or other pituitary hormone deficiencies. Current report presents a child with pituitary stalk transection syndrome who was brought for evaluation of hypoglycemic seizures.

Multiple Endocrine Deficiencies are Common in Hypoparathyroidism–Retardation–Dysmorphism Syndrome

The rare hypoparathyroidism-retardation-dysmorphism (HRD) syndrome (OMIM #241410) is caused by the mutated tubulin chaperone E (TBCE) gene. This gene encodes a critical protein in the microtubule assembly pathway. To evaluate the endocrine profile of patients with HRD. The study used a retrospective analysis of a large cohort of patients in a single university medical center. Sixty-three patients were diagnosed with HRD during 1990 to 2019; 58 of them had an endocrine evaluation. We investigated somatic growth parameters, the prevalence of hypoglycemia, growth hormone deficiency, hypothyroidism, hypogonadism, and cortisol deficiency. All patients were born small for gestational age, and severe growth retardation was found in all patients with mean height standard deviation score (SDS) of -8.8 (range: -5.1 to -15.1) and weight SDS -18 (range: -5.1 to -61.2). Serum insulin-like growth factor-1 concentrations were very low among the 21 studied patients: -2.32 SDS (range: -0.6 to -2.7). Four out of 14 (28%) investigated patients had growth hormone deficiency, and 55% of patients were hospitalized due to symptomatic hypoglycemia. Adrenal glucocorticoid insufficiency was diagnosed in 22% of those tested. Hypothyroidism was found in 36% of patients. Both hypogonadotrophic and hypergonadotrophic hypogonadism were observed. The main magnetic resonance imaging findings were small anterior pituitary gland, small hippocampus, brain atrophy, thin corpus callosum, Chiari type I malformation, and septo-optic dysplasia. Multiple endocrine abnormalities are common in patients with HRD syndrome. Periodic screening of thyroid and adrenal functions is recommended.

SAT-067 Maternal Transmission of Pituitary Stalk Interruption Syndrome(PSIS)

BACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a rare entity characterized by thin or absent pituitary stalk, hypoplastic/aplastic anterior pituitary and ectopic posterior pituitary (EPP) on magnetic resonance imaging (MRI). PSIS can be associated with variable degrees of pituitary insufficiency 1. Most cases of combined pituitary hormone deficiency are sporadic, however in familial cases, there can be AD or AR inheritance with more than 30 genes identified in association with combined pituitary hormone deficiency (CPHD). We describe how diagnosis of 2 children with PSIS led to the discovery of the condition in their mother. Clinical Case: Child 1 presented at age 3yrs with growth failure in 2003 with ht z score -4.24 SD. Subsequent work up revealed low IGF-1 (< 25 ng /mL) and MRI showed EPP, small anterior pituitary gland and absent pituitary stalk. No GH stim test was performed. He was started on GH supplementation and later was diagnosed with central hypothyroidism, central adrenal insufficiency and hypogonadotropic hypogonadism and is doing well on multiple hormone replacement at age 19 yrs.Child 2, a half-brother to child 1 (same mother), presented at age 1yr with growth failure in 2017 with ht z score -2.06. GH stimulation test with glucagon was abnormal and resulted in a very low GH response (peak GH 0.52 ng/mL). MRI showed EPP with small anterior pituitary gland and interruption of the stalk. Later he was found to have central hypothyroidism and mild central adrenal insufficiency. He is receiving standard hormone replacement at 3 yrs of age.Mother of above 2 patients presented 6 mos postpartum in 2017 after her 7th and last pregnancy with fatigue and amenorrhea. Laboratory evaluation revealed central hypothyroidism (FT4 0.76 ng/dL) and she was prescribed levothyroxine followed by resumption of her menses. She was unable to breastfeed her children due to lack of supply. There were no concerns for DI, amenorrhea or infertility. She was referred to Endocrinology in 2019 for persistent fatigue with a question of GH deficiency. IGF-1 level was normal 114 ng/mL(z score -0.39) and GH stimulation test (clonidine + glucagon) was abnormal with peak GH 1.85 ng/ml. MRI showed EPP with hypoplastic pituitary stalk. Genetic testing was done for CPHD Sequencing Panel at Prevention Genetics which includes GL12, HESX1, LHX3, LHX4, OTX2, POU1F1, PROP1F1, PROP1, SOX2, SOX3 genes and results were negative. She has 4 other children (21, 12, 11, 10yrs) who are currently being investigated for hormone deficiencies. One child died at 3 months of age due to SIDS. Conclusion: We present 3 family members with PSIS. This family highlights the variable clinical phenotype of PSIS and importance of careful family history when evaluating children with congenital pituitary abnormalities and supports the need for more extensive gene panels for evaluation of CPHD. Reference:. Acta Endocrinologica, 2017. 13(1):96–105

SAT-289 Evidence That Combined Pituitary Hormone Deficiency Frequently Has a Digenic/Oligogenic Etiology

Congenital hypopituitarism usually occurs in a child without a family history of pituitary disease. Explanations for such sporadic occurrence include: 1) monogenic inheritance (recessive or de novo), 2) digenic/oligogenic inheritance, and/or 3) nongenetic factors. To help distinguish these possibilities, we studied 9 children with hypopituitarism (HP)(small anterior pituitary gland, ectopic posterior pituitary, and either isolated GH deficiency (n=1) or combined with other pituitary hormone deficiencies(n=8)), with non-consanguineous parents and no family history of pituitary disease. SNP array analyses confirmed paternity and non-consanguinity and excluded significant copy-number variation. Exome sequencing was performed in probands and parents. Candidate variants (coverage >10, confirmed by examining BAM files, population frequency <1%, <2 homozygous subjects in gnomAD, and pathogenic prediction by at least 2 out of 3 prediction algorithms (SIFT, MutationTaster, PolyPhen2)) were identified. Children with non-familial non-endocrine idiopathic short stature (ISS) (n=19, sequenced at the same laboratory followed by simultaneous data processing with HP patients), served as a control group. To assess the frequency of genetic (mono-, di-, or oligogenic) HP cases, we identified heterozygous variants (regardless of inheritance) in 42 genes previously reported to be associated with pituitary development. The average number of variants per proband was greater in HP than in ISS (1.1 vs 0.26, P = 0.04). Similarly, the number of probands with at least 1 variant in a pituitary-associated gene was greater in HP than in ISS (67% vs 21%, P = 0.035). These data suggest that sporadic hypopituitarism is frequently genetic. To assess the number of monogenic cases, we counted the number of candidate variants (in any gene in the genome, to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence with a monogenic etiology (de novo mutation, autosomal recessive, X-linked recessive). There were fewer monogenic candidates in subjects with HP than ISS (1.6 vs 2.6 candidates/proband, P = 0.03). These data are consistent with approximately 1.6 non-causative variants/proband in both groups plus approximately 1 causative monogenic variant in ISS vs approximately 0 causative monogenic variants in HP. Candidate variants in genes previously reported to explain the phenotype were identified in 0 out of 9 trios with HP and in 8 of 19 trios with ISS (42%). These findings suggest that a monogenic inheritance is less common in HP than in ISS. In conclusion, the findings suggest that sporadic congenital hypopituitarism is frequently genetic but infrequently monogenic, implying a likely digenic/oligogenic etiology.

SAT-241 Pituitary Stalk Interruption Syndrome Presenting as Neonatal Hypotonia

Pituitary stalk interruption syndrome (PSIS) is a rare condition that include congenital anatomic abnormalities of the pituitary gland and hypopituitarism. There is a wide variety of clinical presentation, with the age at presentation encompassing from neonatal period to adulthood and including one or more pituitary hormone deficiencies. In recent literature there is increasing recognition of PSIS presenting in the neonatal period, mostly involving hypoglycemia. Our patient is a full-term male infant who presented in the newborn period with hypotonia and hypothermia. He also had hypoglycemia, which was initially thought to be associated to hyperinsulinism in the context of gestational diabetes. Micropenis was noted on physical exam. As part of the study for hypotonia, serial thyroid function tests were obtained revealing central hypothyroidism. A low dose ACTH stimulation test was performed which revealed adrenal insufficiency. The patient was started on cortisol and thyroid hormone replacement. Brain MRI showed an ectopic neurohypophysis located along the floor of the hypothalamus, a small anterior pituitary gland, and a partially absent infundibulum, findings consistent with pituitary stalk interruption syndrome. The patient received testosterone injections for micropenis and is being followed for development of other pituitary hormone deficiencies. PSIS is a rare congenital condition that is increasingly recognized in neonates manifesting with signs of hypopituitarism.

Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency.

Recessive mutations in GHRHR are associated with severe isolated growth hormone deficiency (IGHD), with a final height in untreated patients of 130 cm ± 10 cm (-7.2 ± 1.6 SDS; males) and 114 ± 0.7 cm (-8.3 ± 0.1 SDS; females). We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR. Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all three siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the Exome Aggregation Consortium Browser. The brothers were diagnosed with GH deficiency at 9.8 and 6.0 years (height SDS: -2.24 and -1.23, respectively), with a peak GH of 2.9 μg/liter with low IGF-1/IGF binding protein 3. Their sister presented at 16 years with classic GH deficiency (peak GH <0.1 μg/liter, IGF-1 <3.3 mmol/liter) and attained an untreated near-adult height of 144 cm (-3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on magnetic resonance imaging. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100-fold increase in EC50. We report the first coexistence of two novel compound homozygous GHRHR variants in two unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype.

005 – Hypopituitarism in an Infant With Hyperbilirubinemia

005 – Hypopituitarism in an Infant With Hyperbilirubinemia

Hypopituitarism in a Patient With Beckwith-Wiedemann Syndrome Due to Hypomethylation of KvDMR1

Beckwith-Wiedemann syndrome (BWS) is caused by dysregulation of imprinted genes on chromosome 11.p15.5. The syndrome includes overgrowth, macroglossia, organomegaly, abdominal wall defects, hypoglycemia, and long-term malignancy risk. No patient who has BWS has been reported with hypopituitarism. We describe a patient who presented at birth with macrosomia, macroglossia, respiratory distress, jaundice, and hypoglycemia, and who was followed for 4.5 years. Genetic test for BWS was performed, which detected loss of maternal methylation on region KvDMR1 (11p15.5). The hypoglycemia was attributable to hyperinsulinism and was treated with diazoxide and chlorothiazide. She responded well, but the hypoglycemia returned after reducing the diazoxide. It was possible to stop the diazoxide after 2.5 years. On routine follow-up she was noted to be developing short stature. Baseline pituitary and growth hormone (GH) stimulation tests detected GH deficiency and secondary hypothyroidism. A brain MRI showed a small anterior pituitary gland. Thereafter, thyroxine and replacement therapy with GH were started, which resulted in a remarkable improvement in growth velocity. This is the first patient to be reported as having hypopituitarism and BWS. It is unclear if the BWS and the hypopituitarism are somehow connected; however, further investigations are necessary. Hypopituitarism explains the protracted hypoglycemia and the short stature. In our patient, GH therapy seems to be safe, but strict follow-up is required given the increased cancer risk related to BWS.

Pituitary stalk interruption syndrome in 59 children: the value of MRI in assessment of pituitary functions

Pituitary imaging abnormality is a specific indicator of hypopituitarism. This study involved a retrospective review of 59 children diagnosed with pituitary stalk interruption syndrome (PSIS). Of the 59 eligible patients, 54 were born by breech delivery, and there was a significant difference between numbers of patients with breech and head-presenting birth. In order to discuss the relationship between pituitary functions and delineation of pituitary structure in magnetic resonance imaging (MRI), a control analysis was carried out in children with PSIS. Fifty-nine children were subdivided into two groups: group I (partial PSIS, 20 cases) and group II (complete PSIS, 39 cases). There was a significantly small anterior pituitary in both groups of PSIS compared with controls (P < 0.001). The incidence of ectopic posterior pituitary (EPP) was significantly higher in group II (P < 0.001). Before and after hormone replacement therapy, pituitary functions were measured and compared with controls. The levels of growth hormone (GH), free thyroxine (FT4), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and cortisol (COR) were significantly lower in group II (P < 0.05). The dosage of levothyroxine sodium in group II was significantly higher than in group I (P < 0.01). Conclusion. On the basis of birth history, breech presentation may a forewarning for subsequent pituitary hormone deficiencies. Grades of MRI can predict occurrence and severity of PSIS, which are also correlated with the levels of the pituitary target hormone deficiencies. Interruption of pituitary stalk and ectopic posterior pituitary both represent important markers of pituitary structure and function.

The pituitary stalk transection syndrome: multifaceted presentation in adulthood

The pituitary stalk transection syndrome was characterized after introducing the MRI scan in the evaluation of children with hypopituitarism. Its prevalence and natural history into adulthood have not been clearly established. We present 4 cases of stalk transection syndrome diagnosed by the adult endocrinologist that reflect its pleiotropic manifestations. In all cases, MRI showed pathognomonic findings with small anterior pituitary, diminutive or absent infundibulum and ectopic posterior pituitary at the median eminence. Clinical presentation occurred in childhood or the second decade of life. The hormonal deficits were variable in severity and onset, with adrenal insufficiency diagnosed in the second and forth decade in three patients, and absent in another. Growth hormone deficiency was diagnosed before age 10 in three cases and at age 20 in one case with normal spontaneous linear growth. Hypothyroidism had onset in the first or second decade of life and hypogonadism was diagnosed during work-up for lack of pubertal development in all cases. The pituitary stalk transection syndrome should be considered in patients who were previously thought to have idiopathic GH deficiency or multiple pituitary hormone deficiencies. Presence of MRI characteristics compatible with the pituitary stalk transection syndrome should prompt a full pituitary hormonal evaluation. Long-term follow-up by the adult endocrinologist is warranted as new hormone deficiencies might appear later in life.

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.

A Novel Mutation (V101A) of the LHX4 Gene in a Japanese Patient with Combined Pituitary Hormone Deficiency

LHX4, a LIM-homeodomain transcription factor, is required for development of the pituitary and nervous system. Several mutations of the LHX4 gene have been identified in patients with combined pituitary hormone deficiency (CPHD). The objective of the study was to clarify the molecular basis of a Japanese patient of CPHD with a small anterior pituitary and an ectopic posterior pituitary. Genomic DNA was extracted from blood samples of the patient. Exons and exon-intron junctions of the LHX4 gene were amplified and sequenced. An expression vector of the mutant LHX4 protein was constructed and its function was analyzed in vitro. A novel missense mutation (V101A) was identified. IN VITRO transfection studies demonstrated that V101A mutant LHX4 was unable to activate the POU1F1 and FSHbeta subunit gene promoter, indicating a loss of function mutation. Our results identify a novel loss of function mutation of the LHX4 gene in a Japanese patient with CPHD.

Identification of a novel splicing mutation in the growth hormone (GH)-releasing hormone receptor gene in a Chinese family with pituitary dwarfism

A Chinese family with autosomal recessive pituitary dwarfism was identified and the proband was evaluated by MRI and hormonal analysis, which revealed pituitary dwarfism with a complete growth hormone deficiency. MRI showed a pituitary gland with a small anterior pituitary of 2.2 mm and evidence of hypoplastic pituitary. Linkage analysis with markers spanning 17 known genes for dwarfism revealed linkage of the family to the growth hormone-releasing hormone receptor (GHRHR) gene. Mutational analysis of all exons and exon–intron boundaries of GHRHR was carried out using direct DNA sequence analysis. A novel homozygosis mutation, a G to A transition located in the splice donor site at the beginning of intron 8 (IVS8+1G>A), was identified in the proband. The two other patients in the family are homozygous, whereas the living mother of the proband is heterozygous for the IVS8+1G>A mutation. The mutation was not found in 100 normal chromosomes from healthy Chinese individuals of Han nationality. An in vitro splicing assay using HeLa cells transfected with expression vectors containing the normal or the mutant GHRHR minigenes consisting of genomic fragments spanning exons 7–9 showed that the IVS8+1G>A mutation caused abnormal splicing, which is predicted to give rise to truncation or frameshift, leading to severely truncated GHRHR proteins. These results provide strong evidence that the splicing mutation IVS8+1G>A of GHRHR is a cause of pituitary dwarfism in the Chinese family.

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.

Magnetic resonance imaging of the hypothalamus-pituitary unit in childrensuspected of hypopituitarism: who, how and when toinvestigate.

The magnetic resonance (MR) identification of pituitary hyperintensity in the posterior part of the sella has been the most striking recent finding contributing to the diagnosis of "idiopathic" and permanent GH deficiency (GHD). Moreover, advancements in DNA technology have shed new light on the study of the genetic causes of hypopituitarism. Abnormalities in two genes, the GH-N encoding the GH and the GHRH receptor (GHRH-R), have been identified, while mutations in five other gene-encoding transcription factors such as Pit-1, Prop-1, Hesx-1, Lhx-3 and Lhx-4 involved in anterior pituitary development, have also been described. MR imaging shows marked differences in pituitary morphology indicating different GHD etiologies and different prognoses. Ectopic posterior pituitary is a specific marker of permanent GHD. These patients do not have Pit-1, Prop-1, or Lhx-3 mutations and should be carefully monitored for evolving pituitary hormone defects, though they do not require GH re-evaluation in adulthood; selected cases may have Hesx-1 or Lhx-4 mutations. MR evidence of normal or small anterior pituitary gland, enlarged empty sella, pituitary hyperplasia and/or intrasellar or suprasellar mass when associated with combined pituitary hormone deficiency call for molecular analysis of Pit-1, Prop-1, Hesx-1, or Lhx-3. Limitation of neck rotation and Chiari-I malformation may suggest Lhx-3 or Lhx-4 mutations (exceedingly rare). In "idiopathic" isolated GHD, evidence of normal anterior or small anterior pituitary size with normal location of posterior pituitary and normal connection between the hypothalamus and pituitary gland is suggestive of "transitory" or false positive GHD; patients with such characteristics should be re-evaluated well before reaching adult height. In selected cases, anterior pituitary height that is 2 SD below age-adjusted normal pituitary height could be suggestive of GHRH-R gene defect; it is worth pointing out that normal pituitary MR together with severe GHD has been observed, though rarely, in subjects with a genetic origin of GHD.

The spectrum of hypopituitarism caused by PROP1 mutations.

Mutations in the PROP1 gene are responsible for a high proportion of cases of multiple or combined anterior pituitary hormone deficiencies in humans. The physical and hormonal phenotypes of affected individuals are not uniform. The diagnosis is seldom considered during the first year of life. Growth failure is usually evident later in childhood. Deficiency of growth hormone (GH) tends to precede deficiency of thyroid-stimulating hormone (TSH). While most affected individuals fail to enter puberty without sex hormone replacement, some enter puberty but then develop pubertal arrest with a loss of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses to GnRH. Partial deficiency of corticotrophin (ACTH) is a late finding. Imaging of the pituitary may disclose either a small anterior pituitary gland or an intrapituitary mass. The mechanisms responsible for delayed loss of hormone production and the occasional overgrowth of the pituitary represent important areas for future research.

Familial growth hormone deficiency associated with MRI abnormalities

Idiopathic growth hormone deficiency is, in most cases, a sporadic condition. In a number of these patients magnetic resonance imaging (MRI) demonstrates a small anterior pituitary, small or absent pituitary stalk, and ectopically located posterior pituitary. These findings have been attributed to a developmental defect, trauma, or ischemia at birth. We report on a case of familial isolated growth hormone deficiency with mother and son demonstrating the MRI findings described above. The son also had a Chiari type I malformation and medial deviation of the carotid arteries secondary to a narrow skull base. Testing failed to identify a mutation in either the Pit-1 gene or GH gene cluster. This case appears to be an autosomal dominant defect in early development, lending support to the hypothesis that dysgenesis, rather than birth trauma, may cause a small anterior pituitary and ectopic posterior pituitary. Am. J. Med. Genet. 80:128–132, 1998. © 1998 Wiley-Liss, Inc.

Familial growth hormone deficiency associated with MRI abnormalities

Idiopathic growth hormone deficiency is, in most cases, a sporadic condition. In a number of these patients magnetic resonance imaging (MRI) demonstrates a small anterior pituitary, small or absent pituitary stalk, and ectopically located posterior pituitary. These findings have been attributed to a developmental defect, trauma, or ischemia at birth. We report on a case of familial isolated growth hormone deficiency with mother and son demonstrating the MRI findings described above. The son also had a Chiari type I malformation and medial deviation of the carotid arteries secondary to a narrow skull base. Testing failed to identify a mutation in either the Pit-1 gene or GH gene cluster. This case appears to be an autosomal dominant defect in early development, lending support to the hypothesis that dysgenesis, rather than birth trauma, may cause a small anterior pituitary and ectopic posterior pituitary.

Organ- and non-organ-specific auto-antibodies in children with hypopituitarism on growth hormone therapy.

Serum non-organ-specific antibodies (NOSA) against nuclear, mitochondrial (AMA), smooth muscle, liver/kidney microsomal (LKM), reticulin, ribosomal, and organ-specific antibodies (OSA) against pituitary gland, gonads (testis, ovary) adrenal cortex, thyroid (thyroglobulin and microsomal), pancreas islet cells, gastric parietal cells and intestinal epithelial cells were evaluated in 45 patients with hypopituitarism (mean age 12.4 +/- 4.0 years). In 22 of them, 9 with isolated growth hormone (GH) deficiency (IGHD) and 13 with multiple pituitary hormone deficiency, MRI showed anterior pituitary hypoplasia with structural stalk abnormality and ectopic posterior pituitary. Twelve had isolated small anterior pituitary and IGHD and 11 had normal morphology of pituitary gland and IGHD. Controls were healthy age-sex-matched subjects. Thyroid antibodies were detected by a passive haemagglutination test while indirect immunofluorescence was used for the others. The auto-antibodies were found in 7/45 asymptomatic patients, a frequency not significantly different from that in controls; 5 were type NOSA and 2 type OSA. Pituitary antibodies were positive in 1 girl with IGHD and normal pituitary morphology. One girl developed hyperthyroidism during the follow up. Autoantibodies were equally distributed between the three groups and the frequency was not dissimilar from that in controls; this suggests that these patients are not at a higher risk of developing auto-immune disease, at least during the first two decades. Pituitary insufficiency in children with different MRI features seems unlikely to be secondary to an auto-immune process.