Jeremy Kirk

Links Between Granuloma Annulare, Necrobiosis Lipoidica Diabeticorum and Childhood Diabetes: A Matter of Time?

Abstract:  Diabetes mellitus is associated with a range of dermatologic presentations, including granuloma annulare and necrobiosis lipoidica diabeticorum. Granuloma annulare occurs earlier than necrobiosis lipoidica diabeticorum and the association with diabetes mellitus is much weaker. We describe two children with diabetes who both developed granuloma annulare and later, necrobiosis lipoidica diabeticorum. We postulate that the early onset and transient nature of granuloma annulare, compared with the later onset and persistence of necrobiosis lipoidica diabeticorum, might account for the different apparent rates of association with diabetes mellitus.

The identification and measurement of autistic features in children with septo-optic dysplasia, optic nerve hypoplasia and isolated hypopituitarism.

This study aimed to highlight the occurrence of autism spectrum disorders (ASDs) in children with septo-optic dysplasia (SOD) and optic nerve hypoplasia (ONH). A cross-sectional study was designed, including 28 children with SOD and 14 children with ONH. Clinician diagnosis of ASD was reported in 14 children. The Social Communication Questionnaire (SCQ) reported that 23 children met the cut-off point for ASD, and 9 children met the cut-off point for autism. Greater levels of intellectual disability and visual loss were reported in children with ASD in comparison to those without ASD, but, of the two, intellectual disability was a better predictor for ASD. The SCQ lost its sensitivity and specificity in children who had greater visual loss which highlights a requirement for a measure that is sensitive to visual loss. It is also recommended that children with SOD/ONH would benefit from routine screening for ASDs.

KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.

National Audit of Patient Choice in Pediatric GH Therapy

Background: To assess free patient choice for pediatric patients commencing growth hormone (GH) therapy within the UK and Republic of Ireland. Methods: A semistructured questionnaire was sent to all members of the British Society for Paediatric Endocrinology and Diabetes. Results: Of 55 units responding, three do not commence patients on GH. The remaining 52 units included 21 from (all) historic growth centres, 13 from other tertiary centres, and 18 from district general hospitals. 46/52 units (89%) offer free patient choice, involving: demonstration of devices (n = 15), instructional DVDs (6), a combination of both (20), or other (3). Median (range) time spent choosing the GH device was 60 (25–150) min. Device demonstration involved: dialling up doses (39 units), assembling/dissembling (38), GH reconstitution (33), considering facilities provided by manufacturer (25), injecting patient (19), injecting parent (17), showing additional material (11), and cost consideration (4). Median (range) number of steps shown per unit was 5 (1–8), with correlation between numbers of manufacturers/devices and new patients commenced on GH per unit (R = 0.62 and 0.61, both p < 0.01), but not with time spent showing devices (R = 0.12 and 0.22, p > 0.05). Conclusion: Most units now offer some form of patient choice for new patients commencing GH therapy, although this involves several different methods, with larger units offering more manufacturers and more devices.

The relationship between bone mass and body composition in children with hypothalamic and simple obesity

Obesity has been associated with a positive influence on bone mass. This is thought to be due to a mechanical load exerted on the skeleton, together with various hormones and adipocytokines that control appetite and weight, such as leptin, some of which directly affect bone mass. However, there are conflicting reports of the association between fat mass and bone mass in children. Animal studies demonstrate increased bone mass where there is impaired central leptin signalling. Hypothalamic damage can cause abnormal central leptin action, which contributes to the development of obesity.

Galactokinase deficiency in a patient with congenital hyperinsulinism.

BACKGROUND Galactokinase catalyses the first committed step in galactose metabolism, the conversion of galactose to galactose-1-phosphate. Galactokinase deficiency is an extremely rare form of galactosaemia, and the most frequent complication reported is cataracts. Congenital hyperinsulinism (CHI) is a cause of severe hypoglycaemia in the newborn period. Galactosaemia has not previously been reported in a neonate with concomitant CHI. AIMS To report the first case of a patient with CHI and galactokinase deficiency, and to describe the diagnostic pitfalls with bedside blood glucose testing in a neonate with combined galactokinase deficiency and CHI. PATIENTS/METHODS A 3-day-old baby girl from consanguineous parents presented with poor feeding, irritability and seizures. Capillary blood glucose testing using bedside test strips and glucometer showed a glucose level of 18 mmol/L, but the actual laboratory blood glucose level was only 1.8 mmol/L. After discontinuation of oral feeding (stopping provision of dietary galactose), the bedside capillary blood glucose correlated with laboratory glucose concentrations. RESULTS Biochemically the patient had CHI (blood glucose level 2.3 mmol/L with simultaneous serum insulin level of 30 mU/L) and galactokinase deficiency (elevated serum galactose level 0.62 μmol/L). Homozygous loss of function mutations in ABCC8 and GALK1 were found, which explained the patients CHI and galactokinase deficiency, respectively. CONCLUSION This is the first reported case of CHI and galactokinase deficiency occurring in the same patient. Severe hypoglycaemia in neonates with CHI may go undetected with bedside blood glucose meters in patients with galactokinase deficiency.

Disorders of Puberty

Puberty is defined as the time when the onset of sexual maturity occurs and the reproductive organs become functional, and it is therefore the time when a child becomes an adult capable of reproduction. Although the terms puberty and adolescence are commonly used interchangeably, the term puberty tends to be used for the physical, and adolescence for the psychological and social changes.

An association of craniopharyngioma in Turner syndrome

Turner syndrome (TS) (approximately 1:5,000 births) and craniopharyngioma (CP) (1:50,000 children) are both rare conditions. We present three cases of TS with CP, an association not previously described. Visual failure, poor growth or headache led to MRI diagnosis of CP. Whilst two had evidence of hypopituitarism at diagnosis of CP, they all developed hypopituitarism following surgical debulking. Two required radiotherapy due to regrowth. Whether CP and TS share a similar aetiology is unknown. Clinicians need to be aware of this association, and should perform urgent MRI scanning in TS patients with headache, visual impairment or clinical/biochemical evidence of hypopituitarism. Pediatr Blood Cancer 2013; 60: E7–E9.

Understanding precocious puberty in girls

Key content Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls. It is divided into central (gonadotrophin-dependent) precocious puberty and peripheral (gonadotrophin-independent) precocious puberty. Variants of premature sexual development include isolated premature thelarche, premature pubarche and isolated premature menarche (menstruation without other signs of puberty). Possible consequences of precocious puberty include short adult stature due to premature epiphyseal closure and psychosocial problems. Gonadotrophin-releasing hormone analogues are the mainstay of treatment for central precocious puberty. Treatment options vary for peripheral precocious puberty, depending on the underlying aetiology. These include aromatase inhibitors, anti-estrogens, anti-androgens and tumour resection. Combined consultation with or referral to a paediatric endocrinologist is indicated in all cases. Learning objectives To be aware of the normal development and milestones of puberty. To understand the aetiology and diagnostic evaluation of the girl with precocious puberty. To be aware of treatment modalities and multidisciplinary management. Ethical issues Should children with precocious puberty and severe brain dysfunction be given contraception and treated for behavioural problems on parental request?Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls. It is divided into central (gonadotrophin‐dependent) precocious puberty and peripheral (gonadotrophin‐independent) precocious puberty. Variants of premature sexual development include isolated premature thelarche, premature pubarche and isolated premature menarche (menstruation without other signs of puberty). Possible consequences of precocious puberty include short adult stature due to premature epiphyseal closure and psychosocial problems. Gonadotrophin‐releasing hormone analogues are the mainstay of treatment for central precocious puberty. Treatment options vary for peripheral precocious puberty, depending on the underlying aetiology. These include aromatase inhibitors, anti‐estrogens, anti‐androgens and tumour resection. Combined consultation with or referral to a paediatric endocrinologist is indicated in all cases.

Pilot study: Sensory integration processing disorders in children with optic nerve hypoplasia spectrum:

This study aimed to explore the sensory processing profiles of children with the spectrum of optic nerve hypoplasia (ONH). Caregivers completed the Short Sensory Profile (SSP), the Social Communication Questionnaire (SCQ), and the Vineland Adaptive Behaviour Scale (VABS) interview. The study demonstrated that children with ONH present with sensory integration dysfunction (SID), in their intact senses, and that autistic spectrum condition (ASC) was the best predictor of SID, rather than visual loss, or level of intellectual disability in these children. The results indicate that assessment and monitoring of SID in children with ONH is crucial.