Late-onset Hyperinsulinism in an Infant with Beckwith-Wiedemann and Turner Syndromes

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ESPR454
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We report a case of an infant with Beckwith-Wiedemann and Turner syndromes, who had asymptomatic hypoglycemia, uncovered by prolonged fasting for surgical procedure at 9 month of age.

History

The patient is a 9-month-old female with past medical history of Beckwith-Wiedemann (BWS) and Turner syndrome (TS) who presented to an ENT clinic for a scheduled adenoidectomy due to enlarged adenoids causing severe congestion and difficulty breathing. She fasted for twelve hours prior to the procedure. On the day of the procedure, she was noted to be lethargic and a point of care glucose showed hypoglycemia (37 mg/dL). She was treated with oral glucose and discharged with referral to an endocrinologist. Mother was instructed to monitor the child's blood sugars using a home glucometer, which demonstrated episodes of hypoglycemia, 39-46 mg/dL, usually in the morning, approximately five hours after her last feeding. She remained asymptomatic during those episodes. Patient was started on diazoxide 10 mg/kg/day for presumed hyperinsulinism. The dose was subsequently increased to 15 mg/kg/day due to persistently low blood glucose levels.

Her past medical history was significant for being born premature at 36 weeks of gestation. The patient is the third child of nonconsanguineous Caucasian parents. Maternal history is significant for Turner Syndrome. Additionally, the patient has two female siblings, one with Turner syndrome and one with Beckwith-Wiedemann Syndrome.

The patient was admitted to the Neonatal ICU due to transient tachypnea of the newborn and required noninvasive positive pressure ventilation. Infant had transient hypoglycemia and received IV Dextrose, which was gradually weaned over the course of three days. The glucose infusion rate never exceeded 6 mg/kg/min. At three days old the patient was stable on room air and tolerating oral feeds. She passed a four hour fasting challenge and was discharged home. 

After discharge from NICU, follow up consisted of regular abdominal ultrasounds and measurements of serum α-fetoprotein as a surveillance for tumors risk due to BWS.

Physical Exam

The patient was born with a birth weight 3450 grams (92%) and birth length 49.5 centimeters (81%). Of note, placenta's weight was large (>90%) for gestational age. Physical exam was remarkable for macroglossia, ankyloglossia, a high-arched palate and hepatomegaly. No hemihypertrophy or lymphedema were noted at birth.

Laboratory Findings

Mother had amniocentesis at 13 weeks of gestation and the sample was sent for chromosomal analysis, which showed a deletion of the short arm of one X chromosome consistent with Turner syndrome. Furthermore, SNP microarray analysis detected a duplication 11p15.5 with hypermethylation, consistent with a diagnosis of Beckwith-Wiedemann syndrome (BWS).

At birth, patient had hypoglycemia with a blood glucose of 53 mg/dL, thrombocytopenia with platelets of 86 x 10³/μL, and hyperbilirubinemia with a total bilirubin of 6.1 mg/dL at twelve hours of life. Postnatal karyotype showed a terminal deletion at Xp11.4 consistent with Turner syndrome variant.

Outpatient laboratory work-up at 9 month old showed a normal random glucose 73 mg/dL, an insulin of 0.9 uIU/mL, C-peptide of 0.4 ng/mL, and a low-normal HbA1c of 4.8%.

Diagnosis

The reported patient has a combination of two rare genetic disorders, Beckwith-Wiedemann and Turner Syndrome. She had late-onset hyperinsulinism uncovered by prolonged fasting for a surgical procedure. Both Beckwith-Wiedemann and Turner syndromes are implicated in hyperinsulinism and further genetic testing is needed to determine the etiology of hyperinsulinism in this patient.

Discussion

TS is a relatively common type of human chromosomal aberration that occurs in 1 in 2,500 female live births. Most incidences of TS are sporadic and caused by an error in cell division during nondisjunction or during cell division in early fetal development. TS caused by a partial deletion of the X chromosome is a rare exception and may be inherited¹. Though the majority of women with TS are infertile, spontaneous pregnancies have been reported in women with mosaicism and deletion of the distal Xp. The incidence of BWS is estimated to be 1 out of 13,700 and also usually occurs sporadically, with only 15% of cases being inherited². To our knowledge this is the first case report of a patient with coexistent TS and BWS. Additionally, both BWS and TS show familial transmission in this case. Mother of the patient has TS due to 46,X,del(X)(p11.4), the same partial deletion found in our patient and her older sibling, which confirms a familial variant of TS. Given the patient has an older sister with BWS, it is likely that they both inherited the affected 11p15.5, presumably from their shared biological father.

Approximately half of the individuals with BWS have congenital hyperinsulinism. It is associated with mutations in either ABCC8 or KCMJ11 genes that are located on chromosome 11p15.1, proximally to 11p15.5, the region affected in BWS³. Most of these cases are transient, resulting in mild hypoglycemia which usually resolves in the first days to weeks of life⁴.

In addition to being a common symptom of BWS, hypoglycemia secondary to hyperinsulinism is described in TS. Studies by De Leon et al, suggest a 50-fold increase of hyperinsulinism in patients with TS as compared to the general population. Hyperinsulinism in TS is attributed to a haploinsufficiency of the KDM6A gene, located on distal part of the short arm of X-chromosome at Xp11.3. Interestingly, 50% cases of hyperinsulinism reported in Turner syndrome were resistant to diazoxide and required pancreatectomy⁵.

Although our patient had only mild transient hypoglycemia in postnatal period and passed her fasting challenge test, she presented with hypoglycemia at 9 month old. We hypothesize that the patient had persistent hypoglycemia since birth which was compensated by frequent feeds in the neonatal period and was uncovered due to prolonged fasting for surgical procedure. Furthermore, the patient likely was used to having low blood sugars and, therefore, did not exhibit neuroglycopenic symptoms. Hypoglycemia in this case is likely caused by hyperinsulinism. Given our patient has both conditions known to be associated with hyperinsulinism, it is unclear whether in our patient hyperinsulinism is caused by genes involved in BWS or TS. Further genetic testing may be warranted to distinguish the cause of her hyperinsulinism and aid in its management.

References

  1. Turner syndrome: National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2020 Mar 17. Turner syndrome; [reviewed 2017 Oct]; [about 6 screens]. Available from: https://ghr.nlm.nih.gov/condition/turner-syndrome

  2. Hon-Yin BC, Shuman C, Choufani S, Weksberg R. Beckwith-Wiedemann syndrome. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA

  3. Kalish JM, Boodhansingh KE, Bhatti TR, Ganguly A, Conlin LK, Becker SA, et al. Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith-Wiedemann syndrome. J Med Genet. 2016;53:53-61.

  4. Vajravelu ME, De Leon DD. Genetic characteristics of patients with congenital hyperinsulinism. Curr Opin Pediatr. 2018;30:568-75.

  5. Gibson CE, Boodhansingh KE, Li C, Conlin L, Chen P, Becker SA, et al. Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency. Horm Res Paediatr. 2018;89:413-22.

Staten Island University Hospital Northwell Health
Staten Island University Hospital - Northwell Health

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