Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome.

OBJECTIVE: Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder "atypical" GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features. METHODS: Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. "classical" required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), "atypical" required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing. RESULTS: Fifty patients [24 males, 26 females, aged 8.6 +/- 4.6 years (mean +/- SD)] had "classical GHIS", 9 patients (7 males, 2 females, aged 7.8 +/- 4.1 years) had "atypical GHIS", 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS -4.0 +/- 1.4) compared to classical GHIS (-6.7 +/- 1.4), less reduction in IGFBP-3 SDS (atypical -5.5 +/- 3.3; classical -8.6 +/- 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males). CONCLUSIONS: Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.

Endocrine sequelae of childhood craniopharyngioma.

The endocrine sequelae of 62 children with craniopharyngioma were studied retrospectively. These patients were followed for a median duration of 3 years (range 1 to 10 years). Eighteen patients had a long-term follow-up for more than 5 years (range 5 to 10 years). Complete surgical resection was achieved in 30 patients and 32 patients had residual tumor. Twenty-five patients had recurrence or progression of the residual tumor and were treated with radiotherapy. Presenting complaints suggestive of endocrinopathy were infrequent. The most common presenting symptoms were headache, nausea and vomiting, followed by growth failure. Pre-operatively, growth hormone deficiency was the most commonly encountered pituitary hormonal deficiency; however postoperatively, most children had diabetes insipidus. Multiple pituitary hormonal deficiencies were more frequently observed in children treated with extensive radical surgery than in those treated with conservative surgery and radiotherapy. The endocrine morbidity associated with craniopharyngioma and its different management modalities remains high; however, it is manageable with appropriate hormonal replacement therapy.

Three new mutations in the gene for the growth hormone (gh)-releasing hormone receptor in familial isolated gh deficiency type ib.

Isolated GH deficiency (IGHD) is familial in 5-30% of cases. The majority of patients have the type IB form, characterized by autosomal recessive transmission, low but measurable serum concentrations of GH, and responsiveness to exogenous GH therapy. Unique mutations in the gene encoding the GHRH receptor (GHRHR) have previously been described in 2 kindreds with IGHD IB. However, the prevalence of GHRHR mutations in patients with IGHD IB is unknown. We analyzed 30 families with IGHD IB in which more than 1 member was affected. Linkage analysis was performed in 28 of the families, and in 3 families sibling pair analysis indicated linkage to the GHRHR gene locus. These 3 families as well as 2 families in which linkage analysis was not performed were screened for mutations in the 13 coding exons, the intron-exon boundaries, and 327 bases of the promoter of the GHRHR gene. We identified novel GHRHR missense mutations in 2 of the 3 kindreds with informative linkage and in 1 family in which linkage had not been performed. In 1 family affected members were homozygous for a mutation in codon 144 that replaces leucine with histidine (L144H). Affected subjects in a second family were compound heterozygotes, carrying both the L144H mutation and a second mutation in codon 242 that replaces phenylalanine with cysteine. Affected subjects in a third family were homozygous for a mutation that replaces alanine at codon 222 with glutamic acid. All 3 mutations segregated with the IGHD phenotype. All 3 mutant receptors were expressed in CHO cells, and each failed to show a cAMP response after treatment of the cells with GHRH. These results demonstrate that missense mutations in the GHRHR gene are a cause of IGHD IB, and that defects in the GHRHR gene may be a more common cause of GH deficiency than previously suspected.

Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure.

Ten patients with juvenile rheumatoid arthritis (JRA) and growth failure were treated with recombinant human growth hormone (GH) for 1 to 3 years at a dosage of 0.57 IU/kg/wk. All the patients had been on prednisone at a mean dosage of 4.12 mg p.o. daily. GH was low in one patient, two patients had a borderline level and seven patients had adequate response to provocative tests or post-sleep measurement. Serum IGF-I was found to be low in five of six patients. Mean growth velocity increased from 2.45 cm/yr to 4.79 cm/yr after 1 year's treatment with GH (P<0.004). Six patients continued on GH treatment for a second year and continued to have a better growth velocity, with a mean of 5.43 cm/yr (P<0.014). Two patients entered puberty during the second year of GH treatment. This study demonstrates the potential beneficial effect of GH treatment in patients with JRA with growth failure of systemic onset or polyarticular onset who are on prednisone. Further study is needed to determine the long-term effect of GH treatment on ultimate height.

Implantable central venous access devices in children with metabolic disease.

We have inserted 20 totally implantable central venous devices in 17 patients with severe metabolic disease over a 43-month span. Patient ages ranged from 2 months to 17 years (mean, 4.2 years). The underlying pathology was Gaucher's disease in six patients, vitamin D-dependent rickets type II in five, propionic acidemia in two, and methylmalonic acidemia, 3-hydroxyl-3-methylglutaryl coenzyme A (CoA) lyase deficiency, fructose 1,6 diphosphatase deficiency, and urea cycle disorder in one child each. There were seven complications (six due to catheter-related infection and one due to occlusion of the system) during a total of 7,278 patient-catheter days. The infection rate was 0.8 per 1,000 days. Six catheters were removed due to complications and two due to completion of treatment. There were no operative complications or deaths. Our experience demonstrates that a totally implantable device may be useful in children with metabolic disease who need long-term venous access. Attention should be given to minimize the infection rate to reduce the rate of catheter removal.

Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency.

Pit-1, a member of the POU-homeo domain protein family, is one of the transcription factors responsible for anterior pituitary development and pituitary-specific gene expression. Here, we describe seven children with GH, PRL, and TSH deficiency from three, reportedly unrelated, Middle Eastern families, harboring a newly recognized Pro- > Ser recessive mutation in codon 239 of the Pit-1 gene. The mutated residue is located at the beginning of the second alpha-helix of the POU-homeodomain and is strictly conserved among all POU proteins. The Pro239Ser mutant binds DNA normally but is unable to stimulate transcription.

Different faces of non-autoimmune diabetes of infancy.

The aim of this report is to describe four cases of non-autoimmune diabetes that presented in infancy. Three had transient neonatal diabetes mellitus (TNDM) with diabetic ketoacidosis at onset, followed by complete remission after several months of insulin treatment. While the fourth case was initially diagnosed as TNDM, she had renal, hepatic and pancreatic dysplasia. These cases illustrate that diabetes in infants can be difficult to diagnose and that patients with TNDM can have a recurrence of diabetes several years later.

Gender reversal in 46XX congenital virilizing adrenal hyperplasia.

OBJECTIVE: To review the results of gender reversal in six patients with 46XX congenital virilizing adrenal hyperplasia (CVAH). PATIENTS AND METHODS: Fifty-one patients with 46XX CVAH were seen in an 8 year period; 45 were managed by conventional feminizing genitoplasty, but six underwent gender reversal and were managed as males. The clinical decision for gender reversal was made after appropriate counselling and was based primarily on parental choice, this being influenced significantly by a delayed diagnosis in four patients. Surgical management consisted of gonadectomy, excision of Müllerian structures and staged hypospadias repair/ chordee correction in four patients, and circumcision in two completely masculinized children. RESULTS: All six boys are well adjusted to their gender of rearing, with ages ranging from 3 years to 16.5 years (mean 8.5) at the time of review. Two children have normal penises and four have a satisfactory result after two-stage repair of hypospadias/chordee. CONCLUSION: Most patients with 46XX CVAH are preferably raised as females and require a feminizing genitoplasty. However, the clinical decision may be influenced by many factors, including delay in diagnosis, social bias and the premium on male rearing in certain communities. When male rearing is chosen, early gonadectomy and excision of Müllerian structures, together with staged hypospadias repair, gives satisfactory results.

A novel mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Mutations in the vitamin D receptor (VDR) result in hereditary 1,25-dihydroxyvitamin D3-resistant rickets (HVDRR), an autosomal recessive disease caused by target organ resistance to the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. In this study, we investigated the molecular basis of HVDRR in a child from Saudi Arabia who was previously shown to be resistant to 1,25-(OH)2D3 action, but whose cultured skin fibroblasts exhibited normal [3H]1,25-(OH)2D3 binding. Using the PCR, exons 2 and 3 of the VDR gene that encode the DNA-binding region of the receptor were amplified and sequenced. A novel point mutation at nucleotide 252 in exon 2 of the VDR was identified. This missense mutation (GGC to GAC) resulted in the conversion of glycine to aspartic acid at amino acid position 46 (G46D), located at the base of the first zinc finger. This single base change was introduced into wild-type VDR complementary DNA by site-directed mutagenesis, and the mutant VDR was then expressed in COS-1 cells. The expressed mutant VDR displayed a normal binding affinity (Kd = 1.2 x 10(-10) mol/L) for [3H]1,25-(OH)2D3 as determined by Scatchard analysis. However, the mutant VDR was shown to have reduced binding affinity for DNA by DNA-cellulose chromatography. In COS-7 cells cotransfected with a vitamin D response element-chloramphenicol acetyltransferase reporter construct and the mutant VDR complementary DNA expression vector, the mutant VDR was unable to activate gene transcription in cells treated with up to 100 nmol/L 1,25-(OH)2D3. Restriction fragment length polymorphism analysis using MwoI restriction digests of exon 2 demonstrated that the affected child is homozygous for the mutation, whereas the child's father is heterozygous and a carrier of the defective allele. In conclusion, a new mutation was identified in exon 2 of the VDR gene. This mutation, which occurs in the first zinc finger of the DNA-binding domain of the receptor, blocks 1,25-(OH)2D3 action and leads to the syndrome of HVDRR.

Persistent hyperinsulinemic hypoglycemia of infancy: experience with 28 cases.

Twenty-eight infants with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) were seen during a 10-year period. There were 13 males and 15 females. Their age at time of presentation ranged from a few hours to 6 months. Consanguinity was reported in 20 cases (71.4%). One family had two affected siblings and two affected cousins, another had three affected siblings and one affected cousin, and three others had lost siblings because of hypoglycemia and seizures. The primary clinical presentation was jitters and seizures in association with hypoglycemia. The diagnosis was suspected when the therapeutic glucose requirement was found to be more than 12 mg/kg/min and also when there was a good response to glucagon after exclusion of metabolic and storage diseases. A high insulin-to-glucose ratio was noted for all patients. Twenty-two had near-total (90%) pancreatectomy; the result was excellent in all but four, who required supplemental medical therapy. Five patients were treated medically, and one patient's family refused treatment. Twelve patients sustained moderate to severe brain injury before referral. There were no deaths, and only one patient had evidence of malabsorption after the pancreatectomy. PHHI correlates well with consanguinity and family history. Clinical awareness is essential to permit early diagnosis and prompt medical and supportive therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism.

The Institution's experience with hypoglycemia in different types of organic acidemias, branched chain amino acidemia (MSUD), and disorders of fructose metabolism was reviewed retrospectively. The charts of 144 patients who were followed for 1-5 years were studied for the severity and frequency of hypoglycemia. The patients were mainly Saudi; however, 10-25% were from neighboring countries. Therefore, the observations pertain to the genetic groups in the Arabian peninsula. Organic acidemias which primarily manifest with neurologic signs, such as 4-hydroxybutyric aciduria, infantile onset 3-methylglutaconic aciduria, and glutaric aciduria type 1 never showed hypoglycemia. Patients with beta-ketothiolase deficiency, biotinidase deficiency, or intermittent or intermediate MSUD, also did not have hypoglycemia during metabolic crisis. Hypoglycemia was rare and mild among neonates with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia. Less than 50% of the patients with MSUD older than 8 months, pyruvate carboxylase deficiency, methylmalonic acidemia, or propionic acidemia had hypoglycemia during metabolic crisis. On the other hand, patients with 3-hydroxy-3-methyl glutaryl-CoA lyase deficiency, holocarboxylase synthetase deficiency, medium or long-chain acyl-CoA dehydrogenase deficiency, neonatal onset 3-methylglutaconic aciduria, glutaric aciduria type 2, and disorders of fructose metabolism invariably had moderate-to-severe hypoglycemia associated with metabolic crisis. The purpose of this report is to provide the pediatrician, particularly in the Middle East, with a diagnostic guideline to the identification and management of different types of organic acidemias, based on co-existing hypoglycemia.