Monitoring Skull Base Abnormalities in Children with Osteogenesis Imperfecta - Review of Current Practice and a Suggested Clinical Pathway.

OBJECTIVES: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI. METHODS: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging. RESULTS: Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients. CONCLUSION: The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI.

Challenges of delivery of dental care and dental pathologies in children and young people with osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is the most common inherited disorder of bone fragility in children, increasing fracture risk 100-fold and can feature dental and facial bone involvement causing additional morbidities. AIM: To assess the utilisation of tertiary dental services by children and young people with OI attending a supra-regional multi-disciplinary OI service and review of the pathology identified and interventions undertaken. DESIGN: Case notes review of the current caseload of children and young people (0-18 years) with OI at a large regional OI specialist centre (n = 92). Primary outcome was whether an initial dental assessment was arranged in a tertiary dental centre and the corresponding attendance. RESULTS: 49% had a tertiary dental assessment arranged, of whom 82% attended (one quarter requiring several appointments) and 18% did not attend (DNA).Those travelling > 100 miles had a DNA rate of 47%. Assessed children had dentinogenesis imperfecta (24%, 50% in Type III OI), radiographs (95%), caries (41%), required extraction under general anaesthesia (38%) and malocclusion (30%). 48% of the total cohort received bisphosphonates. CONCLUSION: Tertiary dental assessment encountered barriers to uptake of recommended referral in all patients, often due to geographic factors of travel distance, yet when implemented did identify pathology in a large proportion and many resulted in dental intervention. These emphasise the relevance of specialist dental assessment in OI, particularly in the modern context of increased use of bisphosphonates. This is challenging to achieve and several models of delivery of care may need to be considered in this chronic childhood condition.

How does physical activity and fitness influence glycaemic control in young people with Type 1 diabetes?

AIMS: To assess physical activity and fitness levels of young people with Type 1 diabetes compared with siblings without diabetes, and to investigate the association between physical activity, physical fitness and glycaemic control (HbA(1c)) in those young people with diabetes. METHODS: The study consisted of 97 young people aged 8 to 16 years (62% male) from a Paediatric Diabetes Service in South West England. Sixty participants (67% male) had Type 1 diabetes and 37 participants (54% male) were siblings without diabetes (control group). We measured weight, height and waist circumference, calculated BMI and waist-height ratio and recorded pubertal status, blood pressure and current insulin regimen information. We assessed physical activity by accelerometry, from which we calculated light and moderate-to-vigorous intensity activity. We measured physical fitness by multistage sub-maximal bicycle ergometer test. We obtained HbA(1c) by venipuncture. RESULTS: There were no differences between the young people with diabetes and siblings without diabetes in body composition, blood pressure, physical activity and fitness. Moderate-to-vigorous physical activity was associated with better glycaemic control, accounting for 30-37% (R(2) = 0.295-0.374) of the variance for HbA(1c). Physical fitness was not associated with HbA(1c). CONCLUSIONS: Moderate-to-vigorous physical activity was associated with better glycaemic control while fitness was not. Findings suggest that developing strategies to increased moderate-to-vigorous physical activity may prove an effective method of improving glycaemic control in young people with diabetes.

A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.

Autosomal dominant hypocalcaemia with hypercalciuria (ADHH) is an intriguing syndrome, in which activating mutations of the calcium sensing receptor (CaSR) have recently been recognised. We describe a kindred with seven affected individuals across three generations, including patients affected in the first decade of life. Age at diagnosis varied from birth to 50 years. Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia. Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia. Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification, identified by CT scanning in all five individuals. Symptomatic individuals were treated with calcium and calcitriol to reduce the risk of hypocalcaemic seizures. DNA sequence analysis, identified a mutation in exon 3, codon 129 (TGC-->TAC) of the CaSR gene of seven affected family members, resulting in loss of a conserved cysteine residue, potentially disrupting CaSR receptor dimerisation. Thus, a novel mutation was identified in this family, who demonstrate variability of ADHH phenotype and also illustrate the complexities of clinical management. Optimal management of ADHH is difficult and we recommend judicious treatment to avoid an increased risk of nephrocalcinosis.

The IGF-I generation test revisited: a marker of GH sensitivity.

IGF-I generation tests were developed over 20 yr ago and are currently used in differentiating GH insensitivity (GHI) from other disorders characterized by low serum IGF-I. Nevertheless, generation tests have never been adequately characterized, and insufficient normative data are available. One hundred and ninety-eight subjects [including normal subjects; subjects with GHI, GH deficiency (GHD), and idiopathic short stature (ISS); and heterozygotes for the E180 splice GH receptor mutation] were randomized to self-administration of either a high (0.05 mg/kg x d) or a low (0.025 mg/kg x d) dose of GH for 7 d. After a 2-wk washout period, they received the alternate dose. Samples were collected on d 1, 5, and 8 of each treatment period. In normal individuals, IGF-I generation was GH dependent at all ages, and little advantage was observed in using the higher dose of GH or extending beyond the d 5 sample. Some GHD patients had IGF-I levels, both baseline and stimulated, that overlapped levels in the verified GHI patients. Subjects heterozygous for the E180 GH receptor splice mutation did not show a decreased responsiveness to GH. ISS patients had low-normal IGF-I levels that did not stimulate beyond the baseline normative ranges for age. These data provide the first large scale effort to provide preliminary normative IGF generation data and evaluate the GH sensitivity of patients with GHI, GHD, and ISS.

Growth hormone insensitivity: pathophysiology, diagnosis, clinical variation and future perspectives.

The study of genetic growth hormone (GH) insensitivity is an evolving field. GH insensitivity syndrome (GHIS), otherwise known as Laron syndrome, is a heterogeneous disorder. Biochemical features consist of severe insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) deficiency and elevated GH secretion. In a heterogeneous 'European' cohort of GHIS patients, features varied from classical to moderate abnormalities of phenotype and endocrine disturbance. A study of facial features within this series showed that a mild subgroup existed with normal facies, mild short stature and moderate biochemical abnormalities. Overlap with idiopathic short stature (ISS) exists, with heterozygous mutations of the GH receptor demonstrated to cause impaired growth. This 'partial' GHIS has not yet been defined endocrinologically. GH sensitivity, measured by IGF-I and IGFBP-3 responses in the IGF-I generation test, may reveal abnormalities in ISS, although it is likely that the dose of recombinant human GH and frequency of sampling in the test need to be modified.

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.

Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity.

Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 micrograms/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly (p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs.

Binding properties and distribution of insulin-like growth factor binding protein-related protein 3 (IGFBP-rP3/NovH), an additional member of the IGFBP Superfamily.

The protein product of the novH oncogene, a member of the CCN family, is structurally related to the insulin-like growth factor (IGF) binding proteins (IGFBPs). We have characterized aspects of structure, function, and distribution of this protein, which, as IGFBP-related protein 3 (IGFBP-rP3), is a proposed member of the IGFBP Superfamily. Affinity cross-linking experiments performed with baculovirus synthesized recombinant human IGFBP-rP3 established that rhIGFBP-rP3 binds IGF-I, IGF-II, and insulin with low affinity. Specificity of binding was shown by competitive cross-linking experiments; binding to IGF-I and -II was also demonstrated by nondenaturing Western ligand blots. Northern blot analysis indicated the presence of IGFBP-rP3 messenger RNA (mRNA) in a broad range of human tissues. Western immunoblotting studies, using a polyclonal rabbit anti-rhIGFBP-rP3 antibody, demonstrated that IGFBP-rP3 protein is synthesized in vitro by several breast and prostate cancer cell lines: Hs578T, PC3, P69, and LNCaP cells. Western immunoblotting studies of human biological fluids identified that IGFBP-rP3 was present in normal serum, pregnancy serum, serum from patients with growth hormone receptor deficiency, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and follicular fluid, while IGFBP-rP3 fragments were identified in cerebrospinal fluid, amniotic fluid, and prepubertal and pubertal urine samples. Our studies demonstrate that IGFBP-rP3 exhibits IGF binding, albeit at low affinity, and IGFBP-rP3 thus merits inclusion in the IGFBP Superfamily. The low affinity IGF binding suggests that IGFBP-rP3 may act primarily independently of the IGFs. The synthesis of IGFBP-rP3 by several malignant cell lines and its presence in human biological fluids suggest that this protein possesses other interesting roles, potentially in cell growth regulation.

Localization studies of IGFBP-2 and IGFBP-5 in the anterior compartment of the eye.

PURPOSE: Insulin-like growth factor binding proteins (IGFBPs) may modulate insulin-like growth factor-I (IGF-I) action and are important regulating factors in the IGF system. Our aim was to determine the presence of IGFBP-2 and -5 in the anterior compartment of the eye and to compare the histological sites of these IGFBP proteins with the respective IGFBP mRNAs. METHODS: To investigate this, immunohistochemistry was used to detect the presence of IGFBP-2 and -5 proteins, and in situ hybridization was used to determine the presence of IGFBP-2 and -5 mRNAs. The studies were performed in normal adult male Sprague-Dawley rats. Immunohistochemistry was performed by the immunoperoxidase method with polyclonal antibovine-IGFBP-2 and antihuman-IGFBP-5 antibodies. In situ hybridization was performed using 35S-radiolabelled riboprobes. RESULTS: IGFBP-2 mRNA and protein were demonstrated in the outer non-pigmented ciliary epithelium, the corneal germinal epithelium and the corneal endothelium. IGFBP-2 mRNA was detected in these same histological layers of the ciliary processes and the cornea. IGFBP-5 mRNA localized to the stroma and also to the inner pigmented ciliary epithelium and IGFBP-5 protein was demonstrated in the adjacent outer nonpigmented ciliary epithelium. IGFBP-5 mRNA and protein were not demonstrated in the cornea. IGFBPs-2 and -5 were not demonstrated by immunohistochemistry in other structures of the eye. CONCLUSION: We have shown co-localization of IGFBP-2 mRNA and protein and adjacent cellular localization of IGFBP-5 mRNA and proteins in the anterior compartment of the eye. The presence of IGFBP-2 and -5 in the outer ciliary epithelium suggests secretion into the aqueous humour, where they may enhance trapping of IGF-1 which may be important for lens and corneal cell survival. Our studies outlining the site of locally synthesized IGFBPs suggests specific roles in regulation of IGFs and highlights the potential importance of the IGF system in the eye.

CYP11 beta 1 (11-beta-hydroxylase) deficiency in congenital adrenal hyperplasia.

OBJECTIVE: To review experience of CYP11 beta 1 deficiency (previously known as 11 beta-hydroxylase) at the Royal Children's Hospital, Melbourne, Victoria. METHODOLOGY: A retrospective case review was conducted from 1974 to 1995 with five cases identified. RESULTS: Age of presentation ranged from 1 day to 7 years. Presentation was with ambiguous genitalia at birth (two females), simple virilization (two males) and suspected early puberty in mid childhood (one female). Associated clinical features were hypertension (three cases) and tail stature with markedly advanced bone age (four cases). Biochemical abnormalities consistent with CYP11 beta 1-deficiency were elevated urinary tetrahydro-11-deoxycortisol (n = 5) and elevated serum 11-deoxycortisol (n = 3). Additional abnormalities were elevated 17-hydroxyprogesterone (n = 3), elevated androstenedione (n = 4) and elevated dehydroepiandrosterone sulphate (n = 4). The clinical features and investigations suggested CYP11 beta 1-classical deficiency in four patients and CYP11 beta 1-non-classical deficiency in one patient. CONCLUSIONS: The five cases of CYP11 beta 1-deficiency demonstrate a spectrum of clinical abnormalities, with diagnostic difficulties in two cases and delayed presentation in three cases. Prompt diagnosis of CYP11 beta 1-deficiency is facilitated greatly by the availability of a gas chromatography-mass spectrometry instrument and is essential to avoid the long-term effects of hypertension and hyperandrogenism.

Localization of mRNAs for insulin-like growth factor-I (IGF-I), IGF-I receptor, and IGF binding proteins in rat eye.

PURPOSE: To localize mRNAs for insulin-like growth factor (IGF)-I, IGF-I receptor (IGF-IR), and IGF binding protein (BP)-1 to IGFBP-6 in the rat eye. METHODS: cDNA sequences for IGF-I, IGF-IR, and IGFBP-1 to IGFBP-6 were used to synthesize 35S-CTP labeled antisense and sense probes for in situ hybridization on 5-microns sections of the rat eye, including the retina, choroid, sclera, ciliary body, and cornea. RESULTS: IGF-I mRNA was demonstrated over ganglion cells of the retina and endothelial cells of the choroid and ciliary processes. IGF-IR mRNA showed more extensive distribution, localizing to the retinal ganglion cell layer, inner nuclear layer, and outer limiting membrane and also the outer nonpigmented epithelium of the ciliary processes and cornea, conjunctiva, and lens. IGFBP-2 mRNA localized to outer nonpigmented epithelia of the ciliary processes and the germinal layer of corneal epithelium as well as iris, conjunctiva, and sclera. Messenger RNAs for IGFBP-3 to IGFBP-6 localized to choroidal endothelial cells and chromatophores and also to the inner pigmented epithelium of the ciliary processes. Messenger RNAs for IGFBP-5 and IGFBP-6 were seen in the inner and outer nuclear layers of the neural retina. IGFBP-1 mRNA was not detected within the rat eye. CONCLUSIONS: Using in situ hybridization, we have demonstrated mRNAs for IGF-I, IGF-IR, and IGFBP-2 to IGFBP-6 in specific histologic layers of the retina, choroid, ciliary body, and cornea in the rat. The characterization of the IGF system in vivo suggests specific roles in the normal eye and provides a basis for studying the IGF system in eye pathology.

Skeletal dysplasias: response to growth hormone therapy.

OBJECTIVE: This study was conducted to determine the response of children with skeletal dysplasia and short stature to growth hormone therapy and whether such therapy is appropriate in skeletal dysplasia. METHODOLOGY: A retrospective analysis of the Australia-wide group of children with skeletal dysplasia registered on the Ozgrow database, using growth data at commencement and at 12 monthly intervals. Eighteen females and 35 males received growth hormone (GH) therapy for at least 12 months. Patients were aged 10.3 +/- 3.3 (mean +/- s.d.) years and had severe short stature with height standard deviation score (SDS) of -3.5 +/- 1.0 (mean +/- s.d.). RESULTS: Hypochondroplasia (N = 7), metaphyseal dysplasia (N = 5) and dyschondrosteosis (N = 5) were the most frequently represented specific skeletal dysplasia subgroups. These groups and the remaining heterogeneous group did not differ significantly at baseline or subsequent growth response. Duration of GH therapy was mean (range) 36 mo (12-60 mo). Sex, age or degree of short stature did not correlate with response to GH therapy. delta height SDS was 0.3 (mean) after 12 months of GH therapy, which corresponded to an increase in mean growth velocity from 4.3 cm/yr to 6.9 cm/yr. Mean GV declined after the first year, and by 36 months was only 1.1 cm/year above baseline, while delta height SDS was 0.8 CONCLUSIONS: The results suggest that growth hormone therapy is not generally effective for treatment of short stature in skeletal dysplasia.

Renal transplantation in young children.

AIMS: To review the outcome of renal transplantation in small children treated with triple immunosuppression at a single Australian centre. METHODS: The medical records of all children under the age of five years undergoing renal transplantation from 1988 were reviewed. The duration of follow-up was 30 months (range 18-36). RESULTS: Six children received seven renal allografts (five living-related [LR] and two cadaveric [CD]). They had a median age of 3.75 years (range 1.5-4.9) and weight of 11.6 kg (9.1-14.5) at the time of transplantation. All patients received an immunosuppressive regime involving cyclosporin A, azathioprine and prednisolone. There were no deaths. The only graft lost was a CD graft (severe acute rejection within one week of transplantation). Hypertension occurred in all recipients and usually required more than one antihypertensive drug for treatment. Renal function measured by serum median creatinine concentration (range) was 0.05 mmol/L (0.03-0.11) at three months (n = 6) and 0.10 mmol/L (0.07-0.22) at 30 months (n = 4). Growth estimated from median (range) height standard deviation scores was -1.97 (-1.36-(-4.04)) at three months (n = 6) and -1.90 (-1.74-2.50) at 30 months (n = 4). No patient was entirely weaned from prednisolone. Cyclosporin A side effects included hirsutism (five patients), gingival hyperplasia (six patients) and nephrotoxicity (three patients). CONCLUSIONS: Satisfactory patient and graft survival can be accomplished in this recipient age group. The results compare with other international experience and accumulating Australian experience. Hypertension and poor skeletal growth were consistent observations. The long-term outcome of renal function using triple immunosuppression remains to be determined.

The value of flexible bronchoscopy in childhood pulmonary tuberculosis.

The value of 121 flexible bronchoscopy (FB) procedures was evaluated in 54 children, aged three months to 14 years, suspected of having pulmonary tuberculosis. Specimens from FB were culture-positive for Mycobacterium tuberculosis in seven of the 13 bacteriologically confirmed cases. Bronchial abnormalities consistent with the diagnosis were found in 31 of 54 cases. Separate or coexistent findings at initial FB included airway compression (20 cases), granulation tissue (ten cases), and obstructive caseum (four cases). Chest roentgenograms underestimated bronchial involvement in 14 children. Further FB monitoring documented disease evolution. The FB was important in the management of patients, as it (1) guided the use of prednisone therapy, especially in the children with a chest roentgenogram not suggestive of bronchial involvement; (2) indicated a need for resection of granulation tissue by rigid bronchoscopy (three cases); and (3) guided the surgical decision (two children with persistent bronchial obstruction). Thus, FB is a safe and valuable procedure in the management of childhood pulmonary tuberculosis.