Prolactinoma in childhood and adolescence-Tumour size at presentation predicts management strategy: Single centre series and a systematic review and meta-analysis.

OBJECTIVE: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis. PATIENTS AND DESIGN: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%). CONCLUSIONS: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.

Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management.

Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.

Transient neonatal hyperinsulinaemic hypoglycaemia: perinatal predictors of length and cost of stay.

Admission to neonatal care causes separation of infants from their parents, can adversely affect breast-feeding and is associated with painful procedures. Our aim was to identify perinatal factors and cost of care associated with transient neonatal hyperinsulinaemic hypoglycaemia (HH). Infants born after 35 weeks of gestation admitted because of hypoglycaemia were studied. The neonates were divided into two groups (HH and non-HH), and their length and cost of care were compared and perinatal factors predicting those outcomes explored. Forty of the 474 infants admitted with hypoglycaemia were diagnosed with HH. The HH group had a lower median (IQR) glucose level on admission compared to the non-HH group (p < 0.001). The median (IQR) cost of stay was higher in the HH group (p < 0.001). In the HH group, the GIRmax was significantly correlated with cost of stay (p < 0.001). GIRmax predicted a cost of stay > £9140 with an area under the ROC curve of 0.956. GIRmax > 13.9 mg/kg/min predicted admission cost > £9140 with 86% sensitivity and 93% specificity.Conclusion: Transient neonatal HH was associated with a higher length and cost of stay in infants admitted for hypoglycaemia. The GIRmax can predict the length and cost of stay. What is Known: • Neonatal hypoglycaemia is the leading cause of term and late preterm neonatal admissions. • Hyperinsulinism (HH) is the commonest cause of persistent hypoglycaemia, and delay in the diagnosis and management can have a detrimental impact on long-term development. What is New: • We have demonstrated prior to NICU admission that blood glucose concentrations were lower in infants with HH compared to those without. • The maximum GIR had a stronger correlation with total length and cost of hospital stay compared to insulin levels in HH infants.

Neurodevelopmental impairments in children with septo-optic dysplasia spectrum conditions: a systematic review.

BACKGROUND: Septo-optic dysplasia (SOD) is a rare condition diagnosed in children with two or more of the following: hypopituitarism, midline brain abnormalities, and optic nerve hypoplasia. Children with SOD experience varied visual impairment and endocrine dysfunction. Autistic-like behaviours have been reported; however, their nature and prevalence remain to be fully understood. The present systematic review aimed to explore the type and prevalence of neurodevelopmental impairments in children with SOD spectrum conditions. METHODS: The search was conducted in PubMed, EMBASE, and PsycInfo. Hand-searching reference lists of included studies was conducted. All peer-reviewed, observational studies assessing behavioural and cognitive impairments or autism spectrum disorder (ASD) symptoms in children (< 18 years) with SOD, optic nerve hypoplasia, and SOD-plus were included. Studies were excluded if they did not report standardised measures of neurodevelopmental impairments or ASD outcomes. RESULTS: From 2132 screened articles, 20 articles reporting data from a total of 479 children were included in prevalence estimates. Of 14 studies assessing cognitive-developmental outcomes, 175 of 336 (52%) children presented with intellectual disability or developmental delay. A diagnosis of ASD or clinical level of symptoms was observed in 65 of 187 (35%) children across five studies. Only five studies assessed for dysfunction across behavioural, emotional, or social domains and reported impairments in 88 of 184 (48%) of children assessed. LIMITATIONS: Importantly, high heterogeneity among the samples in relation to their neuroanatomical, endocrine, and optic nerve involvement meant that it was not possible to statistically assess the relative contribution of these confounding factors to the specific neurodevelopmental phenotype. This was further limited by the variation in study designs and behavioural assessments used across the included studies, which may have increased the risk of information bias. CONCLUSIONS: This systematic review suggests that the prevalence of neurodevelopmental impairments in children within the SOD spectrum may be high. Clinicians should therefore consider including formal assessments of ASD symptoms and neurodevelopmental impairments alongside routine care. There is, additionally, a need for further research to define and validate a standardised battery of tools that accurately identify neurodevelopmental impairments in SOD spectrum conditions, and for research to identify the likely causal mechanisms.

Pituitary apoplexy in an adolescent male with macroprolactinoma presenting as middle cerebral artery territory infarction.

Pituitary apoplexy typically presents with acute headache, vomiting, visual disturbance, and confusion. Herein, we report a rare presentation of ischemic stroke due to pituitary apoplexy. A 16.5-year-old male presented with reduced Glasgow Coma Scale (GCS) score, slurred speech, right-sided hemiparesis, and bitemporal hemianopia. Magnetic resonance imaging of the brain showed a large hemorrhagic sellar/suprasellar mass and an area of cortical T2/FLAIR hyperintensity with corresponding diffusion restriction in the middle cerebral artery territory. Computed tomography (CT) intracranial angiogram showed luminal occlusion of the clinoid and ophthalmic segments of both internal carotid arteries (ICAs, left>right) due to mass pressure effect. Biochemical investigations confirmed hyperprolactinemia and multiple pituitary hormone deficiencies. Stress-dose hydrocortisone was commenced with cabergoline, followed by urgent endoscopic transsphenoidal debulking of the tumor (subsequent histology showing prolactinoma). Postoperative CT angiogram showed improved caliber of ICAs. Intensive neurorehabilitation was implemented and resulted in complete recovery of motor and cognitive deficits. At the last assessment (18.8 years), the patient remained on complete anterior pituitary hormone replacement without cabergoline. Pituitary apoplexy is a medical emergency requiring prompt recognition and treatment and should be suspected in patients presenting with sudden, severe headache; nausea; or visual disturbance and meningism. Ischemic stroke is a rare manifestation of pituitary apoplexy in the pediatric population.

Central Diabetes Insipidus in Children and Adolescents: Twenty-Six Year Experience from a Single Centre.

Introduction: Paediatric cohorts of central diabetes insipidus (CDI) have shown varying prevalence for different causes of CDI. The objective of this study was to determine the causes of CDI and long-term outcome in children and adolescents from a Tertiary Paediatric Endocrinology unit. Methods: The clinic database was searched to identify patients with CDI managed between 1993 and 2019. Relevant clinical information was collected from patient records. Results: A total of 138 CDI patients, median age 6 years (range <1-18) at presentation, were identified. Principal CDI aetiologies were craniopharyngioma (n = 44), acute central nervous system (CNS) insult (n = 33), germinoma (n = 15), postneurosurgery (indication other than craniopharyngioma and germinoma, n = 20), midline CNS malformation (n = 14), Langerhans cell histiocytosis (n = 5), and familial (n = 2). Idiopathic CDI in this cohort was infrequent (n = 5). Patients with CNS malformations/infections presented with CDI at a younger age compared to patients with CNS tumours (p < 0.0001). Five patients, initially presenting as idiopathic CDI, were subsequently diagnosed with germinoma after a median interval of 3.3 years. All patients with CDI related to craniopharyngioma and nearly all (87%) patients with CDI related to germinoma had concomitant GH, ACTH, and TSH deficiency. The majority of patients who manifested CDI due to acute CNS insult either deceased (30%) or had transient CDI (33.3%). Conclusion: Surgery for craniopharyngioma was the most common underlying aetiology of CDI with ubiquitous occurrence of panhypopituitarism in these patients. Manifestation of CDI in patients with acute CNS insult carries poor prognosis. We affirm that neuroimaging assessment in idiopathic CDI should be continued beyond 3 years from diagnosis as a significant number of patients exhibited progression of infundibular thickening 3 years post-CDI diagnosis.

Autoimmune Encephalitis and Autism Spectrum Disorder.

The concept of "acquired autism" refers to the hypothesis that amongst the massive heterogeneity that encompasses autism spectrum disorder (ASD) there may be several phenotypes that are neither syndromic nor innate. Strong and consistent evidence has linked exposure to various pharmacological and infective agents with an elevated risk of a diagnosis of ASD including maternal valproate use, rubella and herpes encephalitis. Autoimmune encephalitis (AE) describes a group of conditions characterised by the body's immune system mounting an attack on healthy brain cells causing brain inflammation. The resultant cognitive, psychiatric and neurological symptoms that follow AE have also included ASD or autism-like traits and states. We review the current literature on AE and ASD. Drawing also on associated literature on autoimmune psychosis (AP) and preliminary evidence of a psychosis-linked subtype of ASD, we conclude that AE may either act as a potentially causative agent for ASD, and/or produce symptoms that could easily be mistaken for or misdiagnosed as autism. Further studies are required to discern the connection between AE and autism. Where autism is accompanied by regression and atypical onset patterns, it may be prudent to investigate whether a differential diagnosis of AE would be more appropriate.

IgG4-related hypophysitis in adolescence.

OBJECTIVES: IgG4-related hypophysitis is a novel clinical disease entity, which is typically seen in the sixth decade of life and is typically complicated by hypopituitarism. We describe an adolescent female with IgG4-related hypophysitis with normal pituitary function and summarize the relevant literature. CASE PRESENTATION: A 11.8-year-old girl presented with headache and left VI cranial nerve palsy. MRI brain identified an enlarged pituitary gland. Endocrine investigations revealed normal pituitary function. She underwent a transsphenoidal biopsy of the pituitary gland, and histological examination confirmed the diagnosis of IgG4-related hypophysitis. Serum IgG4 concentrations were normal and no evidence of other organ involvement was found. Although the patient tested strongly positive for TB on an interferon gamma release assay, pituitary biopsy was negative for granuloma formation and acid-fast bacilli (Ziehl-Neelson staining). IgG4-related hypophysitis was treated with oral prednisolone and mycophenolate-mofetil with a good response. CONCLUSIONS: We describe to the best of our knowledge, the youngest patient in the published literature with IgG4-related hypophysitis presenting without pituitary insufficiency. A literature review identified only five cases of IgG4-related hypophysitis in adolescence. Serum IgG4 concentrations were normal in all, except one of the adolescent patients reported so far, and appear unhelpful in diagnosis in this age group.

Congenital hyperinsulinism due to mutations in HNF4A and HADH.

Mutations in the HADH and HNF4A genes are rare causes of diazoxide responsive congenital hyperinsulinism (CHI). This chapter details the phenotype known to be associated with mutations in these genes. Additionally, the authors give a brief overview of the role of these genes in glucose physiology and the possible mechanisms of CHI in patients with mutations in these genes.

Acromesomelic Dysplasia, Type Maroteaux: Impact of Long-Term (8 Years) High-Dose Growth Hormone Treatment on Growth Velocity and Final Height in 2 Siblings.

INTRODUCTION: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate limb shortening. It results from loss-of-function NPR2 mutations affecting the C-type natriuretic peptide receptor. Resistance to growth hormone (GH) action has previously been suggested. We describe outcomes of 2 siblings with AMDM after prolonged high-dose GH treatment. PATIENTS/METHODS: Two siblings (Pt-A and Pt-B; consanguineous parents) presented in early childhood with severe disproportionate short stature and radiological features of AMDM. Subsequent genetic testing identified a novel homozygous NPR2 mutation. GH provocation testing showed relatively high GH levels. Serum insulin-like growth factor 1 (IGF-1) was ∼2 SD below age/sex-specific mean. High-dose GH (0.075 mg/kg/day) was started. Pre-GH height velocities were 3.7 (Pt-A) and 4.5 (Pt-B) cm/year. GH dose was adjusted to sustain serum IGF-1 towards +3 SDS for age/sex. Annualized height velocities for first 3 years on GH were 7.0, 5.4, and 4.7 cm/year for patient A and 9.4, 8.0, and 5.9 cm/year for patient B. Height gain during puberty was 10.6 (Pt-A) and 5.9 (Pt-B) cm. Final heights after 8.5 years of GH treatment were 130.5 cm (-6.57 SDS, Pt-A) and 134 cm (-4.58 SDS, Pt-B). CONCLUSIONS: To the best of our knowledge, this is the first report of final height in patients with AMDM after long-term GH treatment. Our results confirm the finding of relative GH resistance in AMDM, which when overcome with high-dose GH treatment resulted in improved height SDS during childhood and adolescence and associated quality of life. The final height of our patients was significantly higher than average reported final height (120 cm) of AMDM patients.

A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome.

Background Inherited severe insulin resistance syndromes (SIRS) are rare and can be caused by mutations in the insulin receptor gene (INSR). Case presentation A 12-year-old Jamaican girl with a BMI of 24.4 kg/m2 presented with polyuria and polydipsia. A diagnosis of T1DM was made in view of hyperglycaemia (18 mmol/l), and elevated Hba1C (9.9%), and insulin therapy was initiated. Over the next 2 years, she developed hirsutism and acanthosis nigricans, and had minimal insulin requirements with frequent post-prandial hypoglycaemia. In view of this, and her strong family history suggestive of a dominantly inherited type of diabetes, the diagnosis was revisited. Targeted next-generation sequencing (NGS) of the patient's monogenic diabetes genes was performed. What is new? NGS revealed a novel heterozygous missense INSR variant, NM_000208.3:c.3471T>G, p.(His1157Gln), confirming a diagnosis of Type A SIRS. Conclusions Type A SIRS can be difficult to differentially diagnose due to the variable phenotype. Features of insulin resistance may be absent at initial presentation and may develop later during pubertal progress. Awareness of the clinical features and comprehensive genetic testing are essential to identify the condition.

Using referral rates for genetic testing to determine the incidence of a rare disease: The minimal incidence of congenital hyperinsulinism in the UK is 1 in 28,389.

Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.

Advances in the diagnosis and management of hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia (HH) is a consequence of unregulated insulin secretion by pancreatic beta-cells and is a major cause of hypoglycemic brain injury and mental retardation. Congenital HH is caused by mutations in genes involved in regulation of insulin secretion, seven of which have been identified (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A). Severe forms of congenital HH are caused by mutations in ABCC8 and KCNJ11, which encode the two components of the pancreatic beta-cell ATP-sensitive potassium channel. Mutations in HNF4A, GLUD1, CGK, and HADH lead to transient or persistent HH, whereas mutations in SLC16A1 cause exercise-induced HH. Rapid genetic analysis combined with an understanding of the histological features (focal or diffuse disease) of congenital HH and the introduction of (18)F-L-3,4-dihydroxyphenylalanine PET-CT to guide laparoscopic surgery have totally transformed the clinical approach to this complex disease. Adult-onset HH is mostly caused by an insulinoma; however, it has also been reported to present as postprandial HH in patients with noninsulinoma pancreatogenous hypoglycemia syndrome, in those who have undergone gastric-bypass surgery for morbid obesity, and in those with mutations in the insulin-receptor gene.

Diabetes mellitus, exocrine pancreatic deficiency, hypertrichosis, hyperpigmentation, and chronic inflammation: confirmation of a syndrome.

Type 1 diabetes mellitus is characterized by dysregulation of the immune system leading to inflammation and selective destruction of pancreatic beta cells. Mild to moderate pancreatic exocrine insufficiency is found in patients with type 1 diabetes. Diabetes mellitus may also be part of a syndrome occasionally involving hair and skin abnormalities. We report our observations on two siblings with insulin-dependent diabetes, severe exocrine pancreatic deficiency, pigmented hypertrichotic skin patches with induration and chronic inflammation. The first sibling presented at the age of 9 months with hypertrichosis and hyperpigmentation, particularly on her back and legs and then developed diabetes mellitus at the age of 4 yr. The second sibling presented with exactly the same clinical features but at a later age of 12 yr. Both siblings had severe pancreatic exocrine deficiency with chronic persistent inflammation. Some of the clinical features in these siblings resemble those described by Prendiville et al. although our patients had additional features. The chronic inflammatory response in both siblings is highly suggestive of some form of immune dysregulation. The presence of consanguinity in the parents and similarity of clinical features in the siblings are suggestive of a novel autoimmune disorder, possibly secondary to autosomal recessive inheritance.

Hyperinsulinism in developmental syndromes.

Hyperinsulinism is a cause of recurrent and severe hypoglycaemia in the newborn and infancy period. Several developmental genetic syndromes are associated with hyperinsulinism. The underlying molecular mechanisms that lead to hyperinsulinaemic hypoglycaemia in most of these syndromes are unclear. Beckwith-Wiedemann syndrome (BWS) is the most common syndrome associated with hyperinsulinism. The incidence of hyperinsulinism in children with BWS is about 50%. The hyperinsulinaemic hypoglycaemia can be transient, which, in the majority of infants, will be asymptomatic and resolve within the first few days of life. Rarely patients with BWS may require a pancreatectomy. Other overgrowth syndromes such as Soto's syndrome may overlap with BWS and present with hyperinsulinism. Patients with other rare syndromes such as Costello, Timothy and Kabuki syndromes can present with hyperinsulinaemic hypoglycaemia but the genetic mechanism(s) that leads to dysregulated insulin secretion in these syndromes is(are) still unclear. The congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic syndromes with a wide symptomatology and severity. They all stem from deficient N-glycosylation of proteins. Hyper-insulinism has been described in congenital disorders of glycosylation, mostly in CDG-Ib but also as the leading symptom in a CDG-Ia patient. In summary, hyperinsulinism may be associated with a large number of developmental syndromes however the underlying molecular mechanisms that cause hyperinsulinism in these syndromes are still unknown.

Exceptional diazoxide sensitivity in hyperinsulinaemic hypoglycaemia due to a novel HNF4A mutation.

Diazoxide is the first-line treatment for patients with hyperinsulinaemic hypoglycaemia (HH). Approximately 50% of patients with HH are diazoxide resistant. However, marked diazoxide sensitivity resulting in severe hyperglycaemia is extremely uncommon and not reported previously in the context of HH due to HNF4A mutation. We report a novel observation of exceptional diazoxide sensitivity in a patient with HH due to HNF4A mutation. A female infant presented with severe persistent neonatal hypoglycaemia and was diagnosed with HH. Standard doses of diazoxide (5 mg/kg/day) resulted in marked hyperglycaemia (maximum blood glucose 21.6 mmol/L) necessitating discontinuation of diazoxide. Lower dose of diazoxide (1.5 mg/kg/day) successfully controlled HH in the proband, which was subsequently confirmed to be due to a novel HNF4A mutation. At 3 years of age, the patient maintains age appropriate fasting tolerance on low dose diazoxide (1.8 mg/kg/day) and has normal development. Diagnosis in proband's mother and maternal aunt, both of whom carried HNF4A mutation and had been diagnosed with presumed type 1 and type 2 diabetes mellitus, respectively, was revised to maturity-onset diabetes of young (MODY). Proband's 5-year-old maternal cousin, also carrier of HNF4A mutation, had transient neonatal hypoglycaemia. To conclude, patients with HH due to HNF4A mutation may require lower diazoxide than other group of patients with HH. Educating the families about the risk of marked hyperglycaemia with diazoxide is essential. The clinical phenotype of HNF4A mutation can be extremely variable. Learning points: Awareness of risk of severe hyperglycaemia with diazoxide is important and patients/families should be accordingly educated. Some patients with HH due to HNF4A mutations may require lower than standard doses of diazoxide. The clinical phenotype of HNF4A mutation can be extremely variable.

Xq27.1 Duplication Encompassing SOX3: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date - A Large Case Series of Unrelated Patients and a Literature Review.

BACKGROUND: Xq27.1 duplication encompassing SOX3 has been implicated in the aetiology of X-linked hypopituitarism associated with intellectual disability and neural tube defects. We describe the largest case series to date of 5 unrelated patients with SOX3 duplication with a variable clinical phenotype, including the smallest reported SOX3 duplication. CASE REPORTS: Five male patients who presented with congenital hypopituitarism (CH) were identified to have Xq27.1 duplication encompassing SOX3. The size of the duplication ranged from 323.8 kb to 11 Mb. The duplication was maternally inherited or de novo in 2 patients each (and of unknown inheritance in 1 patient). The age at presentation was variable. Three patients had multiple pituitary hormone deficiencies, whereas 2 patients had isolated growth hormone deficiency. All patients had micropenis and/or small undescended testes. Structural pituitary and/or other midline cranial abnormalities (callosal hypogenesis/absence of the septum pellucidum) were present in all patients. Two patients had a neural tube defect in addition to CH. CONCLUSIONS: This is the largest series reported to date of unrelated patients with CH in association with Xq27.1 duplication encompassing SOX3. The clinical phenotype is variable, which may be due to genetic redundancy or other unknown aetiological factors. We have expanded the phenotypic spectrum through description of the smallest Xq27.1 duplication (323.8 kb) with CH reported to date, as well as a second family with CH and a neural tube defect.