Severe hypoglycemia with Hyperprolinemia and Pituitary Stalk Interruption Syndrome in a 5-year-old boy: A Case Report and Literature Review

doi:10.21203/rs.3.rs-4629933/v1

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Severe hypoglycemia with Hyperprolinemia and Pituitary Stalk Interruption Syndrome in a 5-year-old boy: A Case Report and Literature Review

https://doi.org/10.21203/rs.3.rs-4629933/v1

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Background: Hyperprolinemia is a rare autosomal recessive disorder with two distinct types: I (HPI) and II (HPII). The clinical presentation varies widely, with some individuals remaining asymptomatic and others exhibiting neurological, renal or auditory defects and seizures. However, it has never been associated with hypoglycemia. The present case report describes a boy with HPII, with an episode of severe hypoglycemia and Pituitary Stalk Interruption Syndrome (PSIS) with isolated growth hormone (GH) deficiency (GHD).

Case presentation: A 5-year and 6/12-month-old boy presented to the Department of Pediatric Endocrinology for routine thyroid function assessment due to hypothyroidism. He was diagnosed as having HPII at the age of 2 years during an investigation for seizure episodes. Clinically, the boy exhibited attention deficit hyperactivity disorder (ADHD) and a reduction in growth velocity (1.6 cm/year). Hematological and biochemical analyses were within the reference range. Hormone profiling revealed lower-than-expected insulin-like growth factor-1 (IGF-1) concentrations, prompting a GH stimulation test, which, in turn, revealed GHD. Brain magnetic resonance imaging (MRI) showed features consistent with PSIS. Noteworthy is the occurrence of severe hypoglycemia during the evaluation, leading to hospitalization, eventually attributed to GHD. Following the exogenous administration of recombinant human GH, the boy exhibited increased growth velocity, with no adverse events over the follow-up period.

Conclusion: Hyperprolinemia is a rare condition; in this context, the occurrence of severe hypoglycemia accompanied by a low growth velocity poses a challenge for the clinical pediatrician.

children

growth hormone deficiency

short stature

orphan disease

aminoacidopathy

inborn error of metabolism

faltering growth

Proline is a key structural protein component, particularly in collagen. It participates in neurotransmitter synthesis, energy metabolism, and antioxidant balance [1]. Hyperprolinemia is a rare autosomal recessive disorder, manifesting in two types, I (HPI) and II (HPII) [1]. HPI results from a deficiency in proline oxidase (PRODH), an enzyme located on chromosome 22 (22q11.21), responsible for converting proline to pyrroline-5-carboxylate (P5C), the initial step in proline-to-glutamate conversion [2, 3]. HPII stems from a deficiency in Δ-1-P5C dehydrogenase activity, a mitochondrial inner-membrane enzyme, with the corresponding gene (ALDH4A1) situated on chromosome 1 (1p36.13) [2, 3]. This deficiency results in pyridoxine depletion and the development of seizures [4]. Exogenous provision of pyridoxine has been suggested to control seizures [5, 6].

In both types of hyperprolinemia, proline concentrations are markedly elevated, 3–5 times higher in HPI and 10–15 times higher in HPII [1]. HPI is biochemically diagnosed through elevated plasma proline without urinary P5C excretion, while the latter in the urine indicates HPII [5]. Enzyme activity assessments and genetic analyses are viable diagnostic approaches [5]. Until now, the co-occurrence of hyperprolinemia, reduced growth rate, and hypoglycemia have not been documented. Herein, we present the case of a patient diagnosed with Pituitary Stalk Interruption Syndrome (PSIS) while exhibiting hyperprolinemia, using the CAse REports (CARE) guidelines [7].

A 5-year and 6/12-month-old boy was presented at the Pediatric Endocrinology Department of Hippokration General Hospital in Thessaloniki for a routine thyroid function assessment due to pre-existing hypothyroidism. His medical history (Fig. 1) revealed HPII, diagnosed at the age of 2 years during an investigation for seizure episodes. The patient was on treatment with thyroxine (24 µg/day). He was born at full term without complications. The birth weight was 3650 g, and the length was 51 cm, with an unremarkable family history. Additionally, the boy had undergone right orchiopexy due to unilateral cryptorchidism, accompanied by microphallus and hypospadias (46,XY disorder of sex development). Regarding dietary supplements, the boy took 100 mg of vitamin B₆ daily, 5 mg of biotin twice daily, 2000 IU of vitamin D daily and 500 mg of L-carnitine daily.

Clinical findings / diagnostic assessment

The boy exhibited a developmental disorder, specifically attention deficit hyperactivity disorder (ADHD), accompanied by a pronounced reduction in growth velocity. Previously, a growth rate of 3.3 cm annually was observed, while during the last six months, the boy had gained only 0.8 cm in height. Comprehensive hematological tests and basic biochemical profiling yielded normal results. Radiological bone age was 2 years and 9/12 months (chronological age: 5 years and 6/12 months). The medical history and clinical investigations pointed towards further investigation of the hypothalamic-pituitary function (Fig. 1). The boy’s hormonal profile is presented in Table 1. Negative results were obtained in celiac disease screening. Due to the low insulin-like growth factor-1 (IGF-1) concentrations, a growth hormone (GH) stimulation test with glucagon was conducted (Table 2).

Table 1

Hormonal profile.
Hormones	Concentrations	Level	Reference range
IGF-1 (ng/mL)	11	↓	37–184
FSH (mU/mL)	2.1	↔	0.4–3.8
LH (mU/mL)	< 0.1	↔	< 0.33
Testosterone (ng/dL)	< 2.5	↔	< 35.7
TSH (µU/mL)	3.05	↔	0.61–4.43
fT₄ (ng/dL)	1.22	↔	1.01–1.63
ACTH (pg/mL)	33.2	↔	7.2–63.6
Cortisol (µg/dL)	19.5	↔	5.3–22.5
Ferritin (ng/mL)	55.9	↔	13.7–78.8
25(OH)D (ng/mL)	28	↔	20–100
Total IgA (mg/dL)	64	↔	21–291
Bold letters denote concentrations out-of-reference range.
ACTH: adrenocorticotropic hormone; fT₄: free T₄; FSH: follicle-stimulating hormone; IGF-1: insulin-like growth factor 1; IgA: immunoglobulin A; LH: luteinizing hormone; TSH: thyroid-stimulating hormone; 25(OH)D: 25-hydroxy-vitamin D₃.

Table 2

Results of the glucagon stimulation test for growth hormone.
Time (min)	Glucose (mg/dL)	Cortisol (µg/dL)	Growth hormone (ng/mL)
0	96	17.3	0.71
30	167	16.6	0.62
60	153	16.2	1.00
90	84	21.9	1.05
120	62	24.9	0.78
150	60	32.0	0.49
180	70	25.1	0.35

Given the GH deficiency (GHD), a magnetic resonance imaging (MRI) of the pituitary was performed, revealing a hypoplastic anterior pituitary lobe (height 2.8 mm), marked thinning of the pituitary stalk, and heightened signal intensity in the posterior pituitary gland (Fig. 2), indicative of pituitary stalk interruption syndrome (PSIS). Before initiating recombinant human GH (rhGH) treatment, the boy experienced a severe episode of hypoglycemia while suffering from gastroenteritis (glucose: 28 mg/dL), necessitating hospitalization. The episode was successfully managed with intravenous administration of glucose.

Therapeutic intervention

After discharge from the hospital, the boy’s blood glucose concentrations were systematically monitored by his parents. Treatment with GH was initiated at a dose of 0.21 mg/kg/week.

Outcome and follow-up (7 months)

Regular communication with the family was maintained to address other potential hypoglycemic episodes or any adverse effects associated with GH administration. Both the patient and his parents were extremely satisfied with the therapy, as the child showed no adverse events and did not encounter additional hypoglycemia episodes. During the scheduled follow-up to evaluate growth velocity at 7 months (5 months post-rhGH-treatment initiation), the boy’s growth velocity increased remarkably, gaining 5.5 cm, resulting in a height of 112.3 cm (Fig. 3).

Proline is a non-essential amino acid found predominantly in collagen. A deficiency in PRODH or P5C dehydrogenase activity (both enzymes belonging to its degradation cascade) results in defective proline metabolism and elevated plasma and/or urine proline concentrations. In 1962, Schafer et al. [8] were the first to document the direct involvement of an error in proline metabolism. The affected family members exhibited hyperprolinemia, cerebral dysfunction, renal anomalies, hereditary nephropathy, and deafness [8].

Since then, there have been only a few reported cases of patients with hyperprolinemia worldwide. The presentation of this condition varies widely, with some individuals remaining asymptomatic [9, 10], while others presenting a diverse range of neurological and/or psychiatric manifestations, as outlined in Table 3. Patients with hyperprolinemia have also been reported to exhibit autism, ADHD, vitamin B₆ deficiency [11], preference for carbohydrate-rich foods and nystagmus. The present case is the first report of a pediatric patient with the co-existence of two rare disorders, HPII and PSIS. The boy was diagnosed with HPII at the age of 2 years, with frequent seizure episodes being the principal manifestation. The manifestation of seizures in HPII may be linked to the neuromodulatory effects of proline and the pro-oxidizing results of P5C [12], as shown in vitro. No specific treatment is advocated due to the benign nature of the condition. However, in patients with associated clinical symptoms, attempts have been made to reduce the endogenous concentration of proline by dietary restriction [13]. More recently, attempts to minimize the pro-oxidant effect of P5C have been recorded, with the provision of per os antioxidant supplementation. In animals [14, 15], hyperprolinemia induces significant oxidative damage to the DNA and antioxidant defense proteins and lipoperoxidation. This result can be controlled by adjuvant antioxidant therapy with vitamins E and C. Furthermore, van de Ven [16] and Walker [11] revealed low vitamin B₆ concentrations in patients with HPII, suggesting mitochondrial dysfunction and the need for supplementary vitamin B₆ intake. This fact indicates that the elevated P5C concentrations in HPII deactivate pyridoxal phosphate (vitamin B₆), a co-factor for several enzymes [11]. For this reason, the present boy was on daily vitamin B₆ supplementation. Even though several dietary manipulations have been applied for hyperprolinemia (Table 4), these are based on individual case reports. The results appear conflicting, as the exact degree of proline and/or protein restriction has not been reported.

Table 3

Clinical characteristics of patients with hyperprolinemia reported in the literature.
First author	Origin	Study design	Sample	Clinical characteristics
Applegarth [24]	Canada	Case report	N = 1, boy with HPII (5-year-old)	Seizures, abnormal EEG
Shivananda [25]	India	Case report	N = 1, infant girl with HPI (2.5-month-old)	Cluster attacks of myoclonic jerks
Di Rosa [26]	Italy	Case series	N = 4, unrelated children with HPI (2–14 years old)	Epilepsy, mental retardation, and behavioral disturbances
Flynn [12]	Ireland	Cross-sectional	N = 312, subjects from 71 families including patients with HPII (N = 63)	Seizures were reported in 17 patients 10 exhibited mental handicap (IQ < 70)
Hama [17]	Japan	Case report	N = 1, boy with HPI (8-year-old)	Preference for carbohydrate-rich foods and tendency toward neurodevelopmental disorders, including autism, ADHD, and learning disorders
Harries [27]	UK	Case report	N = 1, infant with HPI (7-month-old)	Delayed neurological development, abnormalities of the renal tract, EEG and bones, as well as malabsorption
Humbertcalude [28]	France	Case report	N = 1, infant boy with HPI (9-months-old)	Generalized tonic-clonic seizures with fever
Kaur [29]	India	Case report	N = 1, infant girl with HPII (11-months-old)	Recurrent seizures, lethargy, and regression of milestones
Navamar [30]	Netherlands	Systematic review	NR	High prevalence of developmental delay, intellectual disability, autism and psychosis spectrum disorders
Oyanagi [13]	Japan	Case report	N = 1, infant girl with HPI (11-month-old)	Mental and motor retardation
Pavone [31]	Italy	Case series	N = 3, siblings with HPII	Marked hyperprolinemia and hyperglycemia; otherwise asymptomatic
Raux [32]	France	Cross-sectional	N = 92, patients with VCFS, including children (N = 8) with HPI (2–14-year-old)	Mental retardation generalized tonic-clonic seizures and autistic features Higher serum proline concentrations were associated with lower IQ in patients harboring the 22q11 deletion
Steinlin [33]	Switzerland	Case report	N = 1, boy with HPI (10-year-old)	Mental retardation, cerebral palsy, epilepsy, nystagmus
Wajner [34]	Brazil	Case report	N = 1, boy with HPII (5-year-old)	Mild developmental delay, recurrent seizures of the grand mal type
Walker [11]	UK	Case report	N = 1, girl with HPII (18-month-old)	Vitamin B₆ deficiency and convulsions
ADHD: attention-deficit hyperactivity disorder; EEG: electroencephalogram; IQ: intelligence quotient; HPI: hyperprolinemia type I; HPII: hyperprolinemia type II; NR: not reported; SR: systematic review; VCFS: velo-cardio-facial syndrome.

Table 4

Dietary interventions for hyperprolinemia.
First author	Origin	Study design	Population	Intervention type	Intervention duration	Results
Ersoy [35]	Turkey	Case report	N = 1, girl with HPI (4-year-old)	Antioxidant therapy with 100 mg/d co-enzyme Q10 and B complex (B₁ + B₂ + B₆ + B₁₂ vitamins), 500 mg/day of vitamin C, and 500 mg/day L-carnitine	6-month intervention, followed by 1-month wash-out and then revision of intervention	During intervention proline concentrations fell within the reference range. During wash-out, proline concentrations gradually increased, speech impairment increased and fine motor skills were impaired. At 69 months of treatment, IQ and speech disturbance improved significantly.
Goyer [36]	Japan	Case report	N = 1, young girl	Low-proline and low-protein diet NOD, with a mixture of essential amino acids as the sole protein source	1 month	Plasma urea and proline were reduced almost to normal concentrations, and prolinuria lessened. Addition of proline to the diet resulted in an increase in plasma proline. The diet was palatable and well-tolerated.
Harries [27]	UK	Case report	N = 1, infant with HPI (7-month-old)	Restriction of dietary proline NOD	18 months	Fall of plasma proline concentrations within the reference range, satisfactory growth, improved mental development, and the EEG, renal, skeletal, and intestinal abnormalities disappeared.
Ishikawa [37]	Japan	Case report	N = 1, girl with HPI (9-year-old)	Restriction of proline and protein intake NOD		Growth was satisfactory but mental development failed to improve (progressive speech and motor retardation).
Oyanagi [13]	Japan	Case report	N = 1, infant girl with HPI (11-month-old)	Low proline dietary therapy NOD	Since 12-months of age	Serum proline concentrations were decreased reaching the reference range, growth was satisfactory, but mental development did not improve.
EEG: electroencephalogram; HPI: hyperprolinemia type I; IQ: intelligence quotient; NOD, not-other-defined.

Interestingly, the 5-year-old boy displayed a reduction in growth velocity and ADHD symptoms. Despite regular monitoring with anthropometric measurements falling within normal ranges, the abnormal growth velocity was not adequately assessed, resulting in a delayed diagnosis. However, it is important to recognize that children undergo seasonal increases in height, which can further complicate clinical interpretation, so meticulous attention during the clinical evaluation is warranted. Subsequent evaluation involving dynamic GH testing revealed GHD, with normal cortisol secretion. A severe episode of hypoglycemia followed, and then a subsequent brain MRI ultimately led to the diagnosis of PSIS. This raised the concern of whether the hypoglycemia was solely attributed to GHD or was the result of combined factors involving PSIS and hyperprolinemia. In our patient, the absence of subsequent hypoglycemic episodes following treatment with rhGH led to the belief that the primary factor precipitating severe hypoglycemia was GHD. A study by Hama et al. [17] documented an uncommon case of an 8-year-old boy characterized by short stature and suspected hypoglycemia. In this case, hyperprolinemia was identified, and due to normal hypothalamic-pituitary function, short stature was recognized as a clinical manifestation of HPI. It is worth noting that our patient exhibited remarkable growth during his early years. The only clinical indicator prompting investigation for GHD was the lower growth velocity in the absence of overt anomalies in anthropometric parameters relative to the boy’s age.

PSIS consists of an orphan syndrome involving the congenital abnormality of the pituitary gland, with three main characteristics: i) the hypoplastic or inexistent anterior pituitary gland, ii) absent or thin infundibulum, and iii) ectopic posterior pituitary location. PSIS is presented during the first decade of life [18]. Several studies have attempted to explain the mechanisms that induce the triad of anomalies in PSIS. Two primary hypotheses posited for these abnormalities involve traumatic birth injuries (breech delivery, cesarean section, perinatal hypoxemia) and disturbances in the embryonic development of the hypothalamic-pituitary axis [19–21], none of which was applicable in the present case. Identifying familial instances of PSIS and the co-occurrence of central nervous system (CNS) malformations suggest a potential genetic origin, prompting molecular studies aimed at identifying responsible gene mutations [19–21]. However, the family history was unremarkable. Midline CNS malformations infrequently associated with PSIS involve optic nerve hypoplasia, absent septum pellucidum, and Chiari malformation [19–22]. Additional anomalies include micropenis and cryptorchidism [10], the latter observed and being surgically corrected in our case.

Clinically, PSIS manifests as an insufficiency of pituitary hormones, with GHD being universally present at the time of diagnosis [23], as in the case herein. The onset and progression of pituitary hormone deficiencies vary, with common clinical features including delayed growth in childhood and signs of hormonal deficiency at birth being apparent in 30% of cases [23]. The treatment approach involves hormone replacement therapy with GH, thyroxine (T₄), cortisol, estrogen/testosterone, and antidiuretic hormone, according to the needs [14], with long-term follow-up being essential.

In summary, we present the case of a boy with HPII coexisting with PSIS manifesting as GHD, diagnosed due to low growth velocity. The coexistence of these two rare conditions presents a unique medical scenario and poses significant diagnostic challenges. The cause and prevention of severe hypoglycemic episodes in a child with two coexisting conditions before rhGH administration was a diagnostic dilemma. The excellent response to rhGH therapy and the absence of hypoglycemia during further follow-up led to the conclusion that the most decisive factor in the occurrence of the severe hypoglycemic episode was GHD. The value of accurate and regular recording of the anthropometric parameters is emphasized for identifying subtle pathological issues that may require intervention. In that case, they led to further investigations, ultimately revealing the presence of both conditions. This presentation underscores the importance of meticulous clinical evaluation and comprehensive investigative approaches in unraveling complex medical presentations. By shedding light on the complex interplay between rare genetic disorders and their clinical manifestations, this case contributes to the expanding body of knowledge in pediatric endocrinology and it underscores the importance of individualized patient care guided by precise diagnostic approaches.

Informed consent:

Written informed consent was obtained from the patient’s parents/guardian before the study.

Conflict of interest:

The authors declare no competing interests.

Consent to publish:

Written informed consent was provided from the patient’s parents/guardians for publication of this case report and accompanying images.

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Severe hypoglycemia with Hyperprolinemia and Pituitary Stalk Interruption Syndrome in a 5-year-old boy: A Case Report and Literature Review

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Abstract

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Introduction

Case presentation

Clinical findings / diagnostic assessment

Therapeutic intervention

Outcome and follow-up (7 months)

Discussion

Declarations

References

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