Growth hormone deficiency and related disorders: insights into causation, diagnosis, and treatment.

Advances in molecular biology have led to the identification of mutations within several novel genes associated with the phenotype of isolated growth hormone deficiency, combined pituitary hormone deficiency, and syndromes such as septo-optic dysplasia. Progress has also been made in terms of the optimum diagnosis of disorders of stature and their treatment. The use of growth hormone for the treatment of adults with growth hormone deficiency and conditions such as Turner's syndrome, Prader-Willi syndrome, intrauterine growth restriction, and chronic renal failure has changed the practice of endocrinology, although cost-benefit implications remain to be established.

An unusual case of an atypical eating disorder masquerading as a serious multi-systemic illness.

Unlabelled: An early diagnosis and multidisciplinary team approach are mandatory in the management of eating disorders. Serious organic symptoms and nutritional effects can mimic a systemic illness, particularly in those with atypical presentations. A 15-y-old adolescent male presented with poor growth, low weight, abdominal pain and yellow pigmentation.

Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency.

We have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia. We now report the second case of human PC1 deficiency (Subject B), also due to compound heterozygosity for novel missense and nonsense mutations. While both subjects shared the phenotypes of obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones, the clinical presentation of Subject B was dominated by severe refractory neonatal diarrhea, malabsorptive in type.

A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction.

The paired-like homeobox gene expressed in embryonic stem cells Hesx1/HESX1 encodes a developmental repressor and is expressed in early development in a region fated to form the forebrain, with subsequent localization to Rathke's pouch, the primordium of the anterior pituitary gland. Mutations within the gene have been associated with septo-optic dysplasia, a constellation of phenotypes including eye, forebrain, and pituitary abnormalities, or milder degrees of hypopituitarism. We identified a novel homozygous nonconservative missense mutation (I26T) in the critical Engrailed homology repressor domain (eh1) of HESX1, the first, to our knowledge, to be described in humans, in a girl with evolving combined pituitary hormone deficiency born to consanguineous parents.

DNA testing in patients with GH deficiency at the time of transition.

Over the last 10 years, major advances in the understanding of pituitary gland development in the mouse have led to the identification of mutations in a number of genes that then lead to delineation of the phenotype of growth hormone deficiency (GHD), either in isolation (IGHD) or in combination with a number of other hormone deficiencies (CPHD) or syndromic features (e.g., septo-optic dysplasia, SOD).

Septo-optic dysplasia, subglottic stenosis and skeletal abnormalities: a case report.

We report a girl with septo-optic dysplasia in association with subglottic stenosis, sagittal craniosynostosis, osteoporosis and dental anomalies. It is uncommon for patients with septo-optic dysplasia to have multiple, extra-cranial malformations. A number of differential diagnoses were considered in this case, including Cole-Carpenter syndrome, Pfeiffer syndrome and osteoglophonic dwarfism.

Blood pressure in children and adolescents with congenital adrenal hyperplasia (21-hydroxylase deficiency): a preliminary report.

Background: Classical congenital adrenal hyperplasia (CAH) is characterized by a defect in cortisol and aldosterone secretion, adrenal hyperandrogenism, impaired adrenal medullary function and insulin insensitivity. The latter along with the increased tendency towards obesity raises questions whether other cardiovascular risk factors are altered in CAH.

Objective: To evaluate 24-h ambulatory blood pressure and obesity in patients with salt-wasting 21-hydroxylase deficiency diagnosed in the neonatal period and treated with hydrocortisone and 9alpha-fludrocortisone thereafter.

Kinetics and effect of percutaneous administration of dihydrotestosterone in children.

Background: Percutaneous administration of dihydrotestosterone (DHT) has been successful in promoting phallic growth in infants and children with 5 alpha-reductase deficiency raised as males. We investigated whether percutaneous administration of DHT is similarly effective in patients with micropenis due to alternative diagnoses.

Methods: Six patients (age range 1.

Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins.

The androgen insensitivity syndrome (AIS) is the most common cause of male undermasculinization and is typically caused by mutations in the AR gene. Affected individuals may exhibit either complete external feminization (complete AIS) or a partial phenotype (partial AIS). Here we describe monozygotic twins diagnosed with complete AIS who each possess two substitutions (C-->G at position 2930 and T-->C at position 2955, both in exon 7), leading to Phe(856)Leu and Ser(865)Pro mutations, respectively.

Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders.

The homeobox gene Hesx1/HESX1 has been implicated in the establishment of anterior pattern in the central nervous system (CNS) in a number of vertebrate species. Its role in pituitary development has been documented through loss-of-function studies in the mouse. A homozygous missense point mutation resulting in a single amino acid substitution, Arg160Cys (R160C), is associated with a heritable form of the human condition of septo-optic dysplasia (SOD).

Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia.

We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects.

Molecular genetics of septo-optic dysplasia.

Septo-optic dysplasia (SOD) is a highly variable condition characterized by midline neurological abnormalities associated with pituitary hypoplasia and optic nerve hypoplasia. The aetiology is unknown. Mutant mice, in which a novel homeobox gene, Hesx1, has been disrupted, exhibit a phenotype that resembles the phenotype of SOD.

The molecular basis for developmental disorders of the pituitary gland in man.

The development of the anterior pituitary gland is dependent upon a cascade of signalling molecules and developmental genes that function as transcription factors. Many of these genes are homeobox genes which contain a DNA-binding region or homeobox. Animal models have given a valuable insight into human pituitary disease.

Regulation of human GH receptor gene transcription by 20 and 22 kDa GH in a human hepatoma cell line.

The human GH gene is 1.7 kilobase pairs (kb) in length and is composed of five exons and four introns. This gene is expressed in the pituitary gland and encodes a 22 kDa protein.

HESX1: a novel gene implicated in a familial form of septo-optic dysplasia.

The homeobox gene Hesx1, which encodes a pituitary transcription factor, is first expressed at gastrulation in the mouse embryo. Hesx1 expression begins in prospective forebrain tissue but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Transgenic mice lacking Hesx1 exhibit a phenotype comprising variable anterior CNS defects, such as a reduced prosencephalon, abnormalities in the corpus callosum and septum pellucidum, anophthalmia or microphthalmia, defective olfactory development and bifurcations in Rathke's pouch with pituitary dysplasia.

Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency.

Background: Growth hormone insufficiency (GHI) is diagnosed conventionally by short stature and slow growth, and is confirmed by diminished peak GH response to a provocation test. Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) have previously been considered individually

Objective: To test the hypothesis that the combined analysis of IGF-I and IGFBP-3 could act as a surrogate marker for the diagnosis of GHI.

Design: Reference ranges for IGF-I and IGFBP-3 were calculated using 521 normal individuals.

Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse.

During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch.

New growth hormone assays: potential benefits.

Three recently published new assays are described for the measurement of growth hormone (GH). Two of these--the eluted stain assay (ESTA) and the immunofunctional assay (IFA)--have been developed to measure the bioactivity of GH, rather than the immunoactivity as measured by conventional radioimmunoassays (RIAs). The third assay--the 22 kDa exclusion assay (22 k GHEA)--is designed to measure the concentrations of the different isoforms of GH present in the circulation.

Acromegaly or chronic renal failure: a diagnostic dilemma.

Uraemic patients may have markedly elevated serum GH concentrations yet, for hitherto unknown reasons, they do not develop acromegaly. We discuss the diagnostic dilemma presented by a 33-year-old Caucasian male with chronic renal failure (creatinine clearance 10 ml/min) secondary to polycystic kidney disease, elevated GH concentrations (fasting concentration of 22.6 rising to 77.