Recognition of Hyperinsulinaemic Hypoglycaemia in Infants with Congenital Central Hypoventilation Syndrome

Abstract

Introduction

Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant condition due to mutations in the transcription factor PHOX2B. It is characterized by alveolar hypoventilation with symptoms of autonomic nervous system dysfunction. Hyperinsulinaemic hypoglycaemia (HH) due to glucose dysregulation caused by anomalous insulin secretion has been reported as a feature of CCHS. However, HH and glycaemic outcomes in the context of CCHS have not been characterized in longitudinal follow-up. We describe the variable phenotype of glucose dysregulation and glycaemic outcomes in children with CCHS.

Case Presentation

We report 6 children with PHOX2B mutation-positive CCHS diagnosed with HH in a national cohort from two UK congenital hyperinsulinism specialist centres. We describe the initial presentation, the challenges in management, and glycaemic outcomes in longitudinal follow-up. All patients were term infants diagnosed with CCHS in the neonatal period due to PHOX2B mutations and required long-term ventilation by tracheostomy. HH was diagnosed at a median age of 222 days (median, range 36–594) with postprandial hypoglycaemia (4/6 patients) or fasting hypoglycaemia (2/6 patients). Two patients were treated with diazoxide monotherapy; one with diazoxide and overnight continuous gastrostomy feeds; one with acarbose; and two with dietary manifestations and use of continuous glucose monitoring sensor. Three patients who presented earlier in the observation period demonstrated a reduction in the severity of HH over time, leading to hypoglycaemia resolution at a median age of 4.8 years (range 4.45–5.5 years).

Conclusion

Patients with CCHS, due to PHOX2B mutations, may experience both fasting and postprandial hypoglycaemia, necessitating treatment for HH. Clinicians should screen children with CCHS for hypoglycaemia symptoms to quickly identify those affected by HH, initiate prompt treatment, and prevent potential brain injury from severe hypoglycaemia. The severity of hypoglycaemia due to HH tends to decrease over time, with glycaemic resolution potentially being achieved over several years.

Established Facts

• Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant condition caused by mutations in the transcription factor PHOX2B, characterized by alveolar hypoventilation and autonomic nervous system dysfunction.

• Although hyperglycaemia and hyperinsulinaemic hypoglycaemia (HH) have been reported as associated features of CCHS, a comprehensive review detailing the age of onset, biochemical parameters, and treatments is still lacking.

Novel Insights

• Dysregulated glucose homeostasis may be under-recognized in CCHS, often leading to delayed diagnosis of HH, increasing the risk of hypoglycaemic brain injury.

• It is crucial to recognize that patients with CCHS can experience both fasting and postprandial hypoglycaemia. Therefore, screening for HH and initiating prompt treatment are imperative.

• Hypoglycaemia due to HH tends to reduce in severity over time, with glycaemic resolution potentially being achieved over several years.

Introduction

Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant condition of the autonomic nervous system. Many cases of CCHS are due to mutations in PHOX2B, most frequently in polyalanine expansions but sometimes also with frameshift or missense mutations [1, 2]. PHOX2B is a transcription factor with a role in neural crest and embryonic pancreatic development. CCHS is characterized by alveolar hypoventilation with symptoms of autonomic nervous system dysfunction [3]. Patients often experience clinical signs of respiratory compromise and both hyperglycaemia and hyperinsulinaemic hypoglycaemia (HH) have been reported although incompletely characterized [4–11]. The mechanisms underlying glycaemic dysregulation remain uncertain. We present a case series of 6 patients of CCHS associated with HH, aiming to describe the glycaemic phenotype, management challenges, and longitudinal outcome (Table 1).

Table 1.

Clinical features, biochemical investigations, and treatment response in 6 patients with CCHS and HH

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Gestation, weeks	40 + 3	39 + 5	39 + 8	38 + 3	40 + 1	39 + 4
Birth weight, g	2,810	3,160	3,375	Not available	4,450	3,304
Sex	Female	Female	Female	Male	Male	Female
Other clinical features	LTV	LTV	LTV	LTV	LTV	LTV
		Tracheostomy			Tracheostomy
	Tracheostomy	Omphalocele	Tracheostomy	Congenital neuroblastoma	Hirschsprung’s	Hirschsprung’s
		GORD			Myelomeningocele
	Hirschsprung’s	Gastrostomy	Seizures	Gastrostomy	PPH	Ileostomy
	Ileostomy	AD, no fever response
Genetics	PHOX2B expansion (20/27)	PHOX2B expansion (20/26)	PHOX2B expansion (20/27)	PHOX2B c.416A>T;p.Glu139Val	PHOX2B expansion (20/27)	PHOX2B c.416A>C; p.Glu139Ala
Inheritance	Paternally inherited	Unknown	Unknown	De novo	De novo	De novo
Age at HH diagnosis, days	80	36	240	594	204	277
Critical samples at the time of hypoglycaemia	Glucose 2.5 mmol/L	Glucose 1.6 mmol/L	Glucose 2.1 mmol/L	Glucose 1.9 mmol/L	Glucose 2.2 mmol/L	Glucose 2.4 mmol/L
	Insulin <2 mU/L	Insulin 28 mU/L	Insulin 1.7 mU/L	Insulin 2.7 mU/L	Insulin 3.7 mU/L	Insulin <1 mU/L
	C-peptide 237 pmol/L	C-peptide 482 pmol/L	C-peptide 147 pmol/L	C-peptide: N/A	C-peptide 978 pmol/L	C-peptide 284 pmol/L
	NEFA 0.22 mmol/L	NEFA <0.1 mmol/L	NEFA 0.52 mmol/L	NEFA 0.39 mmol/L	NEFA 0.16 mmol	NEFA 0.95 mmol/L
	BHOB 0.92 mmol/L	BHOB 0.3 mmol/L	BHOB <0.05 mmol/L	BOHB 0.27 mmol/L	BOHB <0.05 mmol/L	BOHB 0.59 mmol/L
Diazoxide, max mg/kg/day	Diazoxide (8)	Diazoxide (7)	Diazoxide (11.3)	Diazoxide (7)	Diazoxide (10)	Diazoxide (10)
Chlorothiazide, mg/kg/day	Chlorothiazide (7.5)	Chlorothiazide (7.5)	Chlorothiazide (5.6)	Chlorothiazide N/A	Chlorothiazide (7.5)	Chlorothiazide (7.5)
Response	Responsive	Responsive	Responsive	Unresponsive	Unresponsive	Initially responsive, subsequently partially responsive
Acarbose	N/A	N/A	N/A	N/A	37.5 mg/day	N/A
Response					Responsive
GCMS	N/A	N/A	N/A	CGMS	N/A	CGMS
Feeding regime at discharge	3 hourly daytime oral	3 hourly daytime oral	Demand daytime oral	Gastrostomy feeds and demand oral daytime	Demand daytime oral	Demand daytime oral
	Fasting overnight	Overnight continuous gastrostomy feeds	Fasting overnight	Fasting overnight	Fasting overnight	Fasting overnight
Age of last review	8.5 years	6.5 years	14.2 years	2.7 years	17 months	16 months
HH treatment	None – diazoxide stopped at 4.45 years	None – diazoxide stopped at 4.59 years	None – diazoxide stopped at 5.5 years	Ongoing	Ongoing	Ongoing
Feeding regime at last clinic visit	On demand	On demand	On demand	On demand	On demand	On demand
Fasting tolerance at the last clinic review	13.5 h (max 20 h)	12 h (max 18 h)	12 h	12 h	12 h	12 h

CCHS, congenital central hypoventilation syndrome; HH, hyperinsulinaemic hypoglycaemia; LTV, long-term ventilation; PPH, persistent pulmonary hypertension; AD, autoimmune dysfunction; N/A, not applicable; GORD, gastro-oesophageal reflux disease, CGMS, continuous glucose monitoring sensor.

Case One

A full-term female infant, weighing 2,810 g (−1.34 SDS) at birth, presented during the neonatal period with recurrent apnoea and hypoventilation. She was concurrently diagnosed with Hirschsprung disease and exhibited abnormal heart rate variability, strongly indicating CCHS. Genetic analysis identified a PHO2XB expansion (20/27) inherited from her father, who was a somatic mosaic carrier but was clinically asymptomatic. At 80 days of age, the patient experienced episodes of fasting hypoglycaemia, which were confirmed through a 24-h blood glucose profile (hourly bedside glucose measurements). A standard feed test with critical samples collected a few hours after a nasogastric tube milk feed confirmed the diagnosis of HH. No additional genetic testing for hyperinsulinism was conducted as the PHOX2B defect sufficiently accounted for the phenotype. Treatment was commenced with diazoxide (up to maximum 8 mg/kg/day) and chlorothiazide (7.5 mg/kg/day). She responded well to diazoxide, achieving euglycaemia (bedside blood glucose >3.5 mmol/L) with a 3-hourly feeding schedule. The response to diazoxide was demonstrated according to regional protocols, as indicated by maintaining bedside glucose levels above 3.5 mmol/L during an 8-h fast. Gradually, she outgrew the need for diazoxide and discontinued treatment at 4.5 years of age, after successfully tolerating a 20-h fast without developing hypoglycaemia (bedside and laboratory blood glucose remained above 3.0 mmol/L, in accordance with regional protocols) without the medication. During the most recent clinic visit at 8.5 years, she remains on a normal diet, can tolerate overnight fasting, and has not experienced hypoglycaemic episodes. The patient exhibits mild to moderate learning difficulties and central visual impairment, although her brain MRI did not reveal evidence of ischaemia or hypoglycaemic injury. Interestingly, she was incidentally found to have partial pituitary ectopia though there were no signs of hypopituitarism, and her pituitary function screening tests were normal.

Case Two

A full-term female infant, weighing 3,160 g (−0.54 SDS) at birth, required prolonged ventilation postnatally and was diagnosed with CCHS. Genetic analysis identified a PHO2XB expansion (20/26). At 36 days of age, she experienced a fasting hypoglycaemic episode, confirmed by a 24-h blood glucose profile (hourly bedside glucose measurements) and a standard feed test with critical samples collected a few hours after a milk feed confirmed the diagnosis of HH. No additional genetic testing for hyperinsulinism was conducted as the PHOX2B defect sufficiently accounted for the phenotype. Treatment commenced with diazoxide (up to maximum 7 mg/kg/day) and chlorothiazide (7.5 mg/kg/day). The response to diazoxide was demonstrated in accordance with regional protocols, as evidenced by maintaining bedside glucose levels above 3.5 mmol/L during an 8-h fast. Upon discharge, her feeding regimen included 3-hourly feeds during the day and continuous 7-h feeds via gastrostomy overnight. Over time, she outgrew the need for diazoxide and ceased treatment at 4.5 years of age, after successfully tolerating a 18-h fast without developing hypoglycaemia (bedside and laboratory blood glucose remained above 3.0 mmol/L, in accordance with regional protocols) without the medication. At the last clinic review, she was 6.5 years old, following an on-demand feeding regimen, tolerating overnight fasting without concerns for hypoglycaemic episodes.

Case Three

A full-term female infant, weighing 3,375 g (+1.03 SDS) at birth, was diagnosed with CCHS and required long-term ventilation via tracheostomy. Genetic analysis revealed a PHO2XB expansion (20/27). At 240 days of age, the patient experienced hypoglycaemic seizures, confirmed to be with postprandial HH through investigations (24-h bedside glucose profile and a standard feed test with critical samples collected a few hours after a milk feed). No additional genetic testing for hyperinsulinism was conducted as the PHOX2B defect sufficiently accounted for the phenotype. The patient did not have an age appropriate fast or an overnight record of hypoglycaemia before the diagnosis of hyperinsulinism. Following the introduction of diazoxide, hypoglycaemia reduced, and she was able to fast for 15 h. Longer fast durations were not undertaken due to complex medical problems and other patient factors. Consequently, she was initiated on diazoxide (up to a maximum of 11.3 mg/kg/day) and chlorothiazide (5.6 mg/kg/day). On this treatment, she achieved euglycaemia (bedside blood glucose more than 3.5 mmol/L). The response to diazoxide was demonstrated according to regional protocols, as indicated by maintaining bedside glucose levels above 3.5 mmol/L during a 15-h fast. She gradually outgrew the need for diazoxide and eventually discontinued treatment at the age of 5.5 years after successfully tolerating a 20-h fast without developing hypoglycaemia (bedside and laboratory blood glucose remained above 3.0 mmol/L, in accordance to regional protocols) without the medication. During her last clinic review at 14.2 years of age, she exhibited euglycaemia, followed an on-demand feeding schedule, and tolerated overnight fasting.

Case Four

A full-term male infant (birth weight not available) required postnatal ventilation and was diagnosed with CCHS. Genetic analysis revealed a heterozygous de novo PHOX2B missense variant (c.416A>T, p.Glu139Val), previously unreported in the literature but predicted to have a detrimental effect on protein function and thus be likely pathogenic. Additionally, he was diagnosed with congenital neuroblastoma, managed with chemotherapy and surgical removal. Due to his complex background, he was initiated on gastrostomy feeds during infancy. At 16 months of age, following an increase in the volume of gastrostomy feeds, he experienced multiple episodes of postprandial hypoglycaemia. Investigations including a 24-h hourly bedside glucose measurements, continuous glucose monitoring for 10 days, a diagnostic fasting test, and a standard fed test (his feed, which had previously induced hypoglycaemic symptoms, was administered, and blood glucose levels were monitored for 5 h. Critical samples were collected when the bedside blood glucose fell below 3.0 mmol/L) confirmed postprandial HH, while he demonstrated the ability to fast for 18 h overnight. No additional genetic testing for hyperinsulinism was conducted as the PHOX2B defect sufficiently accounted for the phenotype. Diazoxide was initiated (up to a maximum of 7 mg/kg/day) with suboptimal response as he continued to have hypoglycaemic episodes (bedside blood glucose less than 3.5 mmol/L). Consequently, diazoxide was discontinued, and management continued with gastrostomy feeds alongside a robust glucose monitoring system, including a continuous glucose monitoring sensor (CGMS) and glucometer.

Case Five

A full-term male infant, with a birth weight of 4.45 kg (+2.16 SDS), presented with multiple congenital abnormalities, including open meningomyelocele requiring surgery, persistent pulmonary hypertension, Hirschsprung disease, and ventriculomegaly. There was a family history of a neural tube defect affecting a maternal cousin. CCHS was diagnosed soon at birth. Genetic analysis revealed a PHO2XB expansion (20/27). At 205 days, he developed multiple hypoglycaemic episodes with high glucose requirements (maximum 11.5 mg/kg/min) to maintain euglycaemia. Further investigations including a 24-h hourly bedside glucose measurements, continuous glucose monitoring for 10 days, a diagnostic fasting test, and a prolonged oral glucose tolerance test (oral glucose load was administered at a dose of 1.75 g/kg and blood glucose and insulin samples were taken every 30 min, over a period of 5 h. For this test, hypoglycaemia cut-off point used was 3.0 mmol/L) confirmed postprandial HH, while he was able to fast for 18 h overnight. No additional genetic testing for hyperinsulinism was conducted as the PHOX2B defect sufficiently accounted for the phenotype. Diazoxide was started (maximum 10 mg/kg/day) with careful cardiorespiratory monitoring due to persistent pulmonary hypertension. However, he was unresponsive as he continued to have hypoglycaemic episodes (bedside blood glucose less than 3.5 mmol/L) and diazoxide was stopped after 5 weeks. Acarbose treatment was subsequently initiated alongside the progression of his weaning diet, successfully maintaining euglycaemia.

Case Six

A female infant born at full term with a birth weight of 3.304 kg (+0.04 SDS) was diagnosed with CCHS after genetic analysis revealed a heterozygous likely pathogenic de novo variant in PHOX2B (c.416A>C, p.Glu139Ala), previously unreported in the literature but predicted to be deleterious in silico. Additionally, she was diagnosed with Hirschsprung’s disease, necessitating ileostomy. At 8 months old, she developed hypoglycaemia, confirmed to be due to postprandial HH through investigations including a 24-h hourly bedside glucose measurements, continuous glucose monitoring for 10 days, a diagnostic fasting test, and a standard fed test (her feed, which had previously induced hypoglycaemic symptoms, was administered, and blood glucose levels were monitored for 5 h. Critical samples were collected when the bedside blood glucose fell below 3.0 mmol/L). Diazoxide was initiated with a maximum dosage of 8 mg/kg/day. No additional genetic testing for hyperinsulinism was conducted as the PHOX2B defect sufficiently accounted for the phenotype. Although initial response was positive, 5 weeks later, she was readmitted for stoma prolapse and required adhesiolysis. Subsequently, diazoxide was discontinued, and her management continued effectively through dietary modifications (reducing the volume of bolus nasogastric tube milk feeds, extending the duration of feed administration, transitioning to a solid diet focused on low glycaemic index foods, and high-fibre diet) and a robust glucose monitoring system, including a CGMS and a glucometer.

Discussion

CCHS due to PHOX2B mutations is a complex condition with significant focus of attention devoted to respiratory support through long-term ventilation by tracheostomy. HH has been described in isolated case reports of children presenting with CCHS summarized in Table 2 [4–9]. However, HH is not usually considered in the investigation pathway, unless the child is symptomatic. We have presented a case series of 6 patients from two centres specialized in congenital hyperinsulinism describing the glycaemic phenotype, management challenges, and outcome of HH in CCHS, thereby raising awareness of the need to examine glucose profiles in all patients with CCHS.

Table 2.

Literature review of CCHS and glucose deregulations cases

	Age of presentation	Presentation	Genetics	Treatment	Response
Meissner et al. [4] (2001)	15 months	Postnatal severe apnoea, hypoglycaemia with mild hyperinsulinism	–	Diet	Responded to a carbohydrate-rich diet and diazoxide
				Diazoxide (5 mg/kg/day)
Hennewig et al. [5] (2008)	6 weeks	Episodes of sweating, hypoglycaemia	Gly68Cys mutation in PHOX2B	Diet	Controlled episodes of hypoglycaemia – discontinued at age of 4 months
				Diazoxide (unreported dose)
Farina et al. [6] (2011)
Patient 1	13 days	Seizures	PHOX2B (20/26 genotype)	Diet	Persistence of episodes on diazoxide and so given octreotide – hypoglycaemia controlled after eliminating all simple carbohydrates; octreotide stopped at 16 months of age
				Glucagon (0.5 mg/dL)
				Diazoxide (14 mg/kg/day)
				Octreotide (15 μg/kg/day sc)
Patient 2	8 months	Seizures, hypo episodes at 4 months	PHOX2B (20/26 genotype)	Diet	Glucagon treatment led to hyperglycaemia – controlled on diazoxide until stopped at 22 months; no further seizures reported
				Glucagon (1 mg/day reduced to 0.5 mg/day), then replaced by diazoxide (8–10 mg/kg/day)
Patient 3	15 months	Seizures, hypo episodes at 9 months	PHOX2B (20/26 genotype)	Diet	Diet that prevented fasting for longer than 4 h and diazoxide-controlled episodes – attempts to reduce dose were unsuccessful; child was still on diazoxide after 10 months when reported
				Diazoxide (10 mg/kg/day)
Marics et al. [7] (2012)	14 days	Asymptomatic hypo episodes	PHOX2B (20/27 genotype)	Diet	No improvement on diet and hydrocortisone – started on diazoxide, which reduced episodes
				Hydrocortisone
					Still on 6 mg/kg/day of diazoxide when reported at 7 months
				Diazoxide (10 mg/kg/day – reduced to 6 mg/kg/day at 7 months)
Ganti et al. [8] (2015)	7 months	Apnoea and desaturation, hypoglycaemic seizures	PHOX2B (20/26 genotype)	Diazoxide (7.5 mg/kg/day)	Diazoxide started on 5 mg/kg/day due to parental concerns of hirsutism but episodes persisted and so was increased to 7.5 mg/kg/day – still on treatment when reported
				Hydrochlorothiazide (1 mg/kg/day)
Hopkins and [9] (2016)	5 months	Apnoea, hypercapnia, hypersomnolence, seizure-like episodes, consistently hypoglycaemic	PHO2XB (20/27 genotype)	Diet	Patient experienced hypoglycaemia on diazoxide after withdrawing continuous feeds for just 10 min. Diazoxide stopped at discharge on continuous feeds with glucose checks every 4 h and glucagon to be used as needed
				Diazoxide (20 mg/kg/day)

The underlying cause for HH in CCHS remains unknown. It is hypothesized that the autonomic dysfunction characteristic of CCHS may play a significant role in glucose dysregulation. Specifically, it is proposed that abnormalities in the transcription of the dopamine beta-hydroxylase promoter, responsible for the synthesis of norepinephrine, epinephrine, and octopamine, or dysfunction of the carotid body could contribute to disruptions in glucose regulation and overall body homeostasis [2, 10–13]. Another theory suggests that, during pancreatic development, PHOX2B and Nkx2.2 form a non-cell-autonomous feedback loop that links the neural crest with the pancreatic epithelium. This interaction is thought to regulate the size of the beta-cell population, potentially influencing insulin secretion and energy balance [14]. However, the delayed onset of hypoglycaemia observed in our cohort, with a median onset at 222 days (range 36–594), suggests that a purely pancreatic cause is unlikely as such issues would typically manifest shortly after birth. An additional area warranting investigation is the coexistence of Hirschsprung’s disease in CCHS patients, as previously noted in an infant diagnosed with both CCHS and hypoglycaemia [15]. In our cohort, 3 cases (cases 1, 5, 6) presented with both Hirschsprung’s disease and HH. Despite this, a definitive link between isolated Hirschsprung’s disease and recurrent hypoglycaemia has not been established, highlighting the need for further research. Furthermore, no correlation between genotype and glycaemic phenotype is identified, with patients exhibiting both polyalanine repeat expansions and other mutation types, suggesting that the genomic association with glucose dysregulation may be indirect.

In our cohort, the predominant phenotype was postprandial hypoglycaemia (cases 3, 4, 5, 6), while some patients (cases 1, 2) experienced fasting hypoglycaemia due to hyperinsulinism. We demonstrate that while CCHS-associated HH can manifest shortly after birth with fasting hypoglycaemia, it more commonly presents beyond 6 months of age, primarily exhibiting evidence of postprandial hypoglycaemia. However, cases 1 and 2, who presented with fasting hypoglycaemia and were less than 3 months old, may also have had underlying postprandial hyperinsulinism as differentiating between fasting hyperinsulinism and postprandial hyperinsulinism can be challenging at this age. None of our patients had other known precipitating factors postprandial hyperinsulinism such as gastro-oesophageal reflux surgery (laparoscopic Nissen’s fundoplication), microgastria, vagotomy, pyloroplasty, gastrojejunostomy, oesophageal atresia. This type of HH may either respond to diazoxide or be unresponsive, with some cases successfully managed through alternative treatments such as dietary interventions or acarbose, combined with a robust blood glucose monitoring plan. In our case series, 2 patients were treated with diazoxide monotherapy; one with diazoxide and overnight continuous gastrostomy feeds; one with acarbose; and two with dietary manifestations and use of CGMS. Notably, HH in our infants appeared to become more manageable once a solid oral diet is established. This trend was observed in 3 of our patients (cases 4, 5, and 6), who were older at presentation and were diagnosed with postprandial HH as the cause of their hypoglycaemic episodes. The glycaemic prognosis is positive with a tendency of HH to become less severe, often leading to disease remission, at a median age of 4.8 years (range 4.45–5.5 years), although requiring several years. Regarding the phenotype-genotype correlation, we identified 1 case with a 20/26 polyalanine repeat expansion mutation (PARM), 3 cases with 20/27 PARMs, 2 cases with non-PARMs, and no patients exhibited the milder genotypes of 20/24 or 20/25 PARM. Although our case series of 6 patients of HH and CCHS represents the largest patient cohort with longitudinal follow-up, we acknowledge that our study findings may be biased towards a UK-only perspective and that a larger international cohort will be required to delineate the true long-term natural history of illness. Such a cohort may account for both early and late onset of HH, as described.

In isolated case reports, summarized in Table 2, some studies have described a high incidence of abnormal glucose tolerance in patients with CCHS, characterized by intermittent hyperglycaemia often accompanied by postprandial HH, without fasting-induced hypoglycaemia [10, 11], a feature missing in our patients. It would be important to investigate the tendency to hyperglycaemia over longer periods to identify potential later life diabetes, although specific cases have not yet been described. Similarly, it would be important to investigate if a higher number of polyalanine repeat expansions (20/28) are associated with greater glucose dysregulation, as described in some patients [10].

Conclusion

Our case series demonstrates the need for awareness of hypoglycaemia in all cases presenting with CCHS. Hypoglycaemia may occur both in the fasting and postprandial states and may be treated with a range of options including diazoxide and dietary intervention, with a tendency to resolution after several years. For a fuller evaluation of the natural history of the glycaemic phenotype, a larger cohort with prospective long-term follow-up data from childhood to adulthood is required.

Acknowledgments

The authors thank the patients and their families.

Statement of Ethics

Ethical approval is not required for this study in accordance with local guidelines. Verbal informed consent was obtained for the publication of clinical details and documented in the electronic patient records, in accordance with local guidelines.

Conflict of Interest Statement

I.B. has received in the last 2 years grant support for trials with Zealand, Hanmi, Diurnal, and Crinetics Pharmaceuticals. He is the Chair of the Communications Committee, European Society for Paediatric Endocrinology and Diabetes, and the Chair of the NIHR Clinical Studies Group for Paediatric Endocrinology. A.D. has received grant support for trials with Zealand, Hanmi, and Rezolute. The rest of the authors have nothing to disclose.

Funding Sources

No funding was received for this study.

Author Contributions

Writing – original draft: Malhotra N., Hanania T., and Dastamani A. Writing – review and editing: Yau D., Gilbert C., Morgan K., Wakeling E., Jones W.D., Samuels M., and Banerjee I.

Funding Statement

No funding was received for this study.

Data Availability Statement

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author upon reasonable request.