Hemiparesis With Hypoglycemia in a Child With Hypopituitarism Involving LHX4 Gene Deletion

A 17-month-old boy presented at the emergency department for a 1-day history of right-sided paralysis, decreased speech, and left-side gaze deviation. There was no history of fever, vomiting, diarrhea, seizures, clotting disorders, or drug use.

The patient was born at 39 weeks; his weight was 3120 g and length 48 cm. He had physiologic jaundice with transient hypoglycemia that required intravenous dextrose. Hypoglycemia resolved on the fourth day of life, and he was discharged from the hospital on the fifth day of life. Urology evaluation at 6 months revealed small penile and testicular size. Endocrine evaluation, karyotype, and testicular ultrasound were scheduled, but the patient was lost to follow-up. Motor development and expressive language were delayed (sat without support at 8 months, babbled at 12 months, and pulled to stand at 17 months).

On examination, weight was 8.8 kg (−1.79 SD), length 72 cm (−3.89 SD), temperature 37°C, blood pressure (BP) 86/56 mm Hg, and heart rate 114 beats per minute. The patient was conscious and alert with right-sided weakness of his upper and lower limbs, and his gaze deviated to the left. He also had microphallus (stretched penile length, 2 cm [less than −2.5 SD]) with bilaterally descended testes <1 mL each.

Serum blood glucose (BG) was 41 mg/dL at presentation, increasing to 127 mg/dL after 10% dextrose bolus. Laboratory findings revealed appropriate urine ketones at 1+, high alkaline phosphatase at 7029 U/L (range, 129–291 U/L), and low 25-hydroxy vitamin D at 1.3 ng/mL (range, 30–70 ng/mL). Other laboratory findings were normal, including plasma acylcarnitine profile, complete blood cell count, blood gases, coagulation tests, serum aminotransferases, electrolytes, toxicology screen, and C-reactive protein. Initial MRI revealed a hypoplastic pituitary infundibulum and a markedly hypoplastic pituitary gland within a shallow sella turcica. A possible ectopic area of neurohypophyseal shortening was seen in the expected location of the infundibular recess of the third ventricle. Magnetic resonance angiography (MRA) revealed secondary signs of decreased flow within the left-side middle cerebral artery, suggesting moyamoya syndrome. EEG revealed no seizures but focal slowing and voltage attenuation over the left hemisphere.

The patient became hypotensive after sedation for MRI and needed crystalloid fluid boluses with vasopressors to stabilize his BP. The team was alerted to assess for hypopituitarism by the presence of hypoglycemia, hypotension, and a hypoplastic pituitary gland on MRI, and the patient was started on stress dose hydrocortisone, with sustained improvement seen in BG and BP.

Within 5 hours of admission, the patient was moving all his limbs with no neurologic deficit. Repeat MRA 24 hours after presentation revealed normal results. Cerebral angiogram, cerebrospinal fluid chemistry, brain computed tomography scan, and MRA findings were normal. The resolution of hemiparesis within hours of treatment with dextrose-containing fluid and normalization of brain vascular abnormalities within 24 hours of presentation suggested hypoglycemia as the underlying etiology.

Additional endocrine investigation confirmed that the patient’s hypoglycemia was secondary to panhypopituitarism, with low random cortisol during hypoglycemia (4.71 μg/dL; range, 3–21 μg/dL), low insulin-like growth factor I (15 ng/mL; range, 30–122 ng/mL), low insulin-like growth factor binding protein 3 (0.34 mg/L; range, 1.29–3.63 mg/L), low free thyroxine (0.58 ng/mL; range, 0.80–2.00 ng/mL), and inappropriately normal thyroid stimulating hormone (1.6 μIU/mL; range, 0.500–4.500 μIU/mL). Electrolyte levels were normal, with average daily urine output of 3 mL/kg/day during admission, making it less likely that he had diabetes insipidus.

Genetic evaluation was requested because of the clinical findings. Chromosomal microarray revealed a male genomic profile with a pathogenic 145-kb microdeletion of GRCh37 1q25.2q25.3(180167266_ 180312524)x1 (Invitae). This microdeletion contains 2 annotated genes in Online Mendelian Inheritance in Man: LHX4 and ACBD6. LHX4 has been implicated in CPHD4,²  and both heterozygous pathogenic variants and microdeletions have been described. The size of microdeletion involving the LHX4 gene that we found in the patient was much smaller than those previously reported (0.5 Mb and 1.5 Mb).^2,3 ACBD6-related clinical changes have only been recently reported in 2 cases of developmental delay, but with biallelic pathogenic variants (autosomal recessive). Thus, a deletion of 1 copy of the gene would be expected to confer carrier status only.

The patient was placed on a physiologic dose of hydrocortisone with thyroxine replacement, and he completed a 12-hour safety fast with BG maintained >70 mg/dL before discharge from the hospital. Growth hormone (GH) replacement was started as outpatient.

Hypoglycemic symptoms are classified as autonomic symptoms (sweating, tremors, feelings of warmth, anxiety, and tingling) and neuroglycopenic symptoms (dizziness, confusion, difficulty in speaking, headache, inability to concentrate, convulsion, transient hemiparesis, and coma). Transient hypoglycemic hemiparesis (HH), though regularly reported in adults,^4–7  is an uncommon presentation of hypoglycemia in the pediatric population.

Most reported cases of HH in childhood are in the settings of diabetes mellitus, accidental ingestion of hypoglycemics,⁸  hyperinsulinism,⁹  or hypoglycemia of unknown etiology^10,11  (Table 1). However, we could not find an earlier report of HH secondary to hypopituitarism.

Less than 3% of cases of CPHD are estimated to be associated with pathogenic variants or gene deletions of the LHX4 gene.³  The LHX4 gene directs the synthesis of a transcription factor that regulates early embryonic development of the anterior pituitary gland.¹² 

In childhood, GH deficiency is a rare cause of hypoglycemia, with a prevalence of 1 in 4000¹³  compared with diabetes mellitus (0.28–2.42 in 1000)¹⁴  or hyperinsulinism (up to 1 in 2500).¹⁵  GH and cortisol are mainly involved in maintaining euglycemia during intermediate and prolonged fasting by reducing insulin sensitivity and glucose utilization while increasing positive nitrogen balance and lipolysis.¹⁶  GH deficiency becomes apparent a few hours into fasting and is associated with insufficient ketosis from reduced glycerol and free fatty acid, with defective alternative substrate generation¹⁷  predisposing to an exaggerated risk of brain damage in a developing brain.

In the index case we describe and as with most patients, HH is often misdiagnosed as cerebrovascular accident. Initial assessment frequently involves an extensive evaluation for cerebrovascular accident with no evaluation for an endocrine etiology. The delay or lack of endocrine evaluation in an acute setting could be because most patients who present with HH also have a history of diabetes mellitus; however, 9 of the 19 reported cases of HH were in children and adolescents without diabetes mellitus (Table 1). Therefore, focal cerebral symptoms with hypoglycemia should warrant an endocrine evaluation in an acute setting. Regardless of the cause of hypoglycemia, the onset of hemiparesis in HH is usually acute and transient, resolving after administration of intravenous glucose usually within a few hours to a few days.^1,21–24 

Unlike in adult reports of HH where there is a predilection for right-sided hemiparesis,^5–7,25  reports of HH in children have revealed a comparable predilection between the right and left cerebral hemisphere, sometimes affecting alternating lobes in the same person with recurrent HH²⁶ ; however, the mechanism underlying HH is poorly understood. Different from our patient with a hypoplastic pituitary gland, none of the 19 previously reported cases revealed an underlying brain abnormality. Our patient had an initial MRA finding suggestive of moyamoya syndrome that resolved on subsequent imaging. Kossoff et al¹⁶  reported on a 12-year-old female patient with an EEG finding of focal slowing without seizure, and a similar EEG pattern was seen in our patient, but the exact process underlying these transient brain abnormalities is still unknown.

The pathomechanism of various long-term neurologic sequelae of hypoglycemia is from neuroactive amino acids released during hypoglycemia causing neuronal necrosis with eventual neuronal death,²⁷  but this is not so in transient focal hypoglycemic hemiparesis. Proposed theories for the underlying mechanism of HH include selective hemispheric cerebral hypoperfusion,²⁵  cerebral vasospasm,²⁸  and change in hypoglycemic tolerance of the neurons.²⁹  These hypotheses might explain HH seen in some adults because some of the reported cases are of adults with underlying cardiovascular risk factors^5–7,25,28 ; however, a more probable hypothesis for HH in children is neuronal susceptibility without an underlying focal brain injury.¹ 

To our knowledge, this case report is the first of childhood HH secondary to pituitary hormone deficiency and the first of transient HH-induced focal neurologic deficit with complete normalization of the previous MRA abnormality suggestive of moyamoya syndrome. Hemiparesis in a child should raise suspicion for hypoglycemia-induced transient hemiparesis, and the importance of measurement of the BG level early in presentation cannot be overemphasized. Because imaging studies can reveal normal or abnormal findings and cannot be used to differentiate between hypoglycemia and stroke, prompt diagnosis and treatment with additional endocrine evaluation are essential to prevent permanent neurologic damage.

BG

blood glucose

BP

blood pressure

CPHD4

combined pituitary hormone deficiency type IV

GH

growth hormone

HH

hypoglycemic hemiparesis

MRA

magnetic resonance angiography