A novel mutation in the ABCD1 gene of a patient with X-linked adrenoleukodystrophy presenting with central precocious puberty: a case report

doi:10.21203/rs.3.rs-3126998/v1

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by the variations in the ATP-binding cassette sub-family D member 1 (ABCD1) gene located on the X-chromosome, leading to an accumulation of very long chain fatty acids (VLCFAs), which impair many tissues, including the cerebral white matter, the spinal cord, and the adrenal cortex. However, no study has reported central precocious puberty (CPP ) in individuals with X-ALD. A 6-year-old proband presented with pigmentation of the skin and mucosa, elevated levels of plasma adrenocorticotropic hormone and VLCFAs, and no neurological dysfunctions. He had rapid growth in height velocity, testicular size of 5–6 mL, and penile length of 6 cm. A novel variant, c.1826A > G (p.Glu609Gly), was identified in exon 8 of the ABCD1 gene.

ABCD1

ALDP

VLCFAs

X-linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is aperoxisomal disorder caused by variations in the ATP-binding cassette sub-family D member 1 (ABCD1) gene located on the X-chromosome, leading to the absence or dysfunction of ABCD1 (also known as ALDP ).[1] The deficiency of ALDP can result in impaired peroxisomal β-oxidation of saturated very long chain fatty acids (VLCFAs ), and consequently, its accumulation in tissues, including the cerebral white matter, the spinal cord, and the adrenal cortex.[2] According to neurological symptoms, age of onset, and progression of illness, patients with X-ALD can be clinically classified into seven categories: childhood cerebral, adolescent cerebral, adrenomyeloneuropathy (AMN), olivopontocerebellar, Addison’s disease, asymptomatic type and presymptomatic type.[3] Childhood cerebral ALD and AMN are the two most common phenotypes. For decades, some patients have been diagnosed with Addison's disease with adrenal insufficiency for decades.[4]

Central precocious puberty (CPP) is characterized by the appearance of any sign of secondary sexual maturation before the age of 8 years in girls and 9 years in boys, resulting from the activation of the hypothalamic-pituitary-gonadal axis.CPP has not yet been reported in patients with ALD. Here, we report the case of a boy diagnosed with Addison’s disease and CPP. A novel variant, c.1826A > G (p.Glu609Gly), in exon 8 of the ABCD1 gene of the proband was identified.

A 6 year and 8 month old boy was referred to our hospital because of a slow progressive skin pigmentation that started o from around the age of 5 years. The skin pigmentation was noticed initially on the elbows and knee, gradually spread to the whole-body skin, tongue, ear, tooth, and gum. The patient had a transient coma during once cold with vomiting and diarrhea several times. He had no difficulties with vision, hearing, motions, or intelligence. A neurological examination revealed no abnormalities. His uncle died from diarrhea at 1 year of age, and his maternal granduncle had paralysis at approximately 40 years of age.

His height was 124.5cm (Z score, 0.39), weight 23.5kg (Z score, 0.04), and body mass index 15.16 kg/m² (Z score, -0.21). He had a rapid growth rate during the past year, increasing by 8cm. Pubertal examination revealed a testicular size of 5–6 mL, and a penile length of 6cm with sparse pubic hair. Random luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were 0.4 IU/L, 1.1 IU/L, and < 0.07 ng/mL, respectively. The bone age was 8 years and 4 months. Further GnRH stimulation tests reported that the peak levels of LH was 12.5 IU/L and FSH 3.1I U/L. The boy was considered to have precocious puberty because of the accelerated growth, enlargementof the testis, appearance of secondary sex characteristics, and elevated LH before 9 years of age.

Cortisol at eight o'clock was 61.7 nmol/L (adrenal insufficiency: <83 nmol/L; adrenal insufficiency excluded: > 414.6 nmol/L). The plasma adrenocorticotropic hormone (ACTH) level was more than 2000.0 pg/mL (reference range,[< 46 pg/mL]). ACTH stimulation experiment showed that cortisol levels at 0, 30, and 60 minutes were 69.2, 61.7, and 68.6 nmol/L, respectively (reference range,[> 500 nmol/L was normal]), and 17-hydroxyprogesterone levels at 0, 30, and 60 minutes were 0.1, 0.5, and 1.2 nmol/L, respectively. The plasma VLCFAs assay revealed the following results: C26:0, 0.398 µmol/L (normal range, 0.008–0.085 µmol/L); C24:0, 0.319 µmol/L (normal range, 0.015–0.172 µmol/L); C24:0/C22:0 ratio, 1.195 (normal range, 0.124–1.087), and C26:0/C22:0 ratio, 5.307 (normal range, 0.183–2.316), suggesting elevated plasma VLCFAs levels. Magnetic resonance imaging of the brain, hypophysis, and adrenal gland revealed normal findings.

Whole-exome sequencing of the peripheral blood of the proband revealed a novel variant, c.1826A > G (p.Glu609Gly), in exon 8 of the ABCD1 gene. The inheritance mode was X-linked Recessive; and the proband was hemizygous, and the mother was heterozygous. This variant was classified as a variant of uncertain based on the American College of Medical Genetics criteria.[5] Multiple softwarepackages, such as Polyphen_HVAR, LRT, and Mutation Taster, were used to predict the effect of variants. This variant was predicted to be damaging with a score of 0.977.The patient has been doing well with glucocorticoid replacement therapy, with whole-body pigmentation in remission. The patient did not show any significant neurological disorders.

The study was approved by the Ethics Committee of West China Second Hospital, Sichuan University. Written informed consent was obtained from the patient and his parents.

The clinical spectrum of X-ALD is very broad, but three main phenotypes can be distinguished including the childhood cerebral form, adrenomyeloneuropathy (AMN), and ‘Addison disease only.” The childhood cerebral form and AMN are hard to miss because their initial manifestations are intellectual deterioration, attention deficit hyperactivity disorder, and vision, hearing, and motor impairment.

Here, we report a case of skin pigmentation without paraparesis, walking difficulties, or cerebellar ataxia. The age of onset was approximately 6 years. The clinical diagnosis of X-ALD was based on the skin pigmentation,adrenal insufficiency, and high levels of plasma VLCFAs levels.

Onset of “Addison disease only” in males can range from 2 years of age to adulthood, but commonly before 7.5 years, without evidence of neurological abnormality.[6] Signs include unexplained vomiting, weakness, and coma due to insufficient cortisol and hyperpigmentationdue to increased ACTH by negative feedback. Although the boy had symptoms of vomiting and coma initially but he was diagnosed with adrenocortical insufficiency until hyperpigmentation of the skin and increased plasma VLCFAs levels helped to confirm the clinical diagnosis of X-ALD. X-ALD is likely under-diagnosed in boys with adrenal insufficiency [7], and in one study, 83% of boys with unexplained adrenal insufficiency had X-ALD [8]. Almost all male X-ALD patients had increased plasma VLCFAs levels, regardless of clinical severity, and; this was also true for 85% of female carriers.[9] Therefore, testing plasma VLCFAs levels provides an opportunity for screening patients with X-ALD.

To date, more than 750 different variants of the ABCD1 gene have been listed in the ALD Mutation Database.[10] However, no clear genotype-phenotype correlations have been identified. In the present study, whole- exome sequencing analysis revealed a novel variant, c.1826A > G (p.Glu609Gly), in exon 8 of the ABCD1 gene in the proband. His uncle and maternal grand uncle had a history of suspected X-ALD without performing the DNA analysis.

In the present study, the boy was diagnosed with X-ALD and CPP. The underlying mechanism of the activation of the hypothalamic-pituitary-gonadal (HPG) axis and subsequent entry timely into puberty is complicated and has not yet been fully clarified. Specific genetic mutations, central nervous system diseases, some rare syndromes, sex steroids exposure, and environmental factors are the major causes of CPP. The correlation between X-ALD and precocious puberty was very confusing. To the best of our knowledge, the disturbance of VLCFAs can result in hypogonadism. [11] Testicular dysfunctions detected in X-ALD male adults with elevated FSH and LH levels, and lower testosterone levels,[11] while no detectable signs of testicular insufficiency were found in prepubertal patients with ALD.[12] Instead of hypogonadism,our patient developed CPP; this is the first CPP case reported in ALD. Höftberger et al. investigated the expression of ABCD1 in a broad range of human tissues and found that ALDP was also strongly expressed in the hypothalamus, apart from the subcortical and cerebellar white matter in the brain,[13] which might be the reason for disturbances in the HPG axis in patients with X-ALD. We hypothesized that the CPP in boys with X-ALD might develop into partial testicular dysfunction in adults, which requires further follow-up.

In conclusion, we report a case of X-ALD in a boy with CPP. A novel variant of the ABCD1gene has been identified. VLCFAs analysis is important for ALD diagnosis. It is necessary to evaluate and follow-up on sexual development in patients with ALD.

Acknowledgements: Not applicable.

Authors' contributions: TTZ and MXS conceptualized and drafted the initial manuscript; JW and MXS conceptualized the initial manuscript and critically revised the manuscript; TTZ wrote the initial manuscript and critically revised the manuscript; MXS helped with the therapy and follow-up of the patient and revised the initial manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding:No funding was used for the creation of this manuscript.

Availability of data and materials: All data supporting the findings of this article are included in the manuscript.

Ethics approval and consent to participate: Not applicable.

Consent for Publication: Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing Interest: The authors declare that they have no competing interests.

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Table 1. Clinical characteristics of the reported patient whohad central precocious puberty at the diagnosis of ALD
Characteristics	Value	Characteristics	Value
Age at diagnosis, years	6	Serum ACTH, pg/ml	>2000
Height, cm (SDS)	124.5 (0.39)	Serumcortisol at eight o’clock, nmol/L	61.7
Weight, kg (SDS)	23.5 (0.04)	Serum LH, IU/L	0.4
Body mass index, kg/m2 (SDS)	15.16 (-0.21)	Serum FSH, IU/L	1.1
Bone age, years	8	Serum 25-hydroxyvitamin D, ng/mL	30.4
Testicular volume, mL	5-6	Serum calcium, mmol/L	2.34

Table 2.Very Long Chain Fatty Acid Level (μmol/L) in the Patient and Reference Values
C20:0-LPC	0.267	0.031-0.404
C22:0-LPC	0.075	0.008-0.119
C24:0-LPC	0.319↑	0.015-0.172
C26:0-LPC	0.398↑	0.008-0.085
C24/C20	1.195↑	0.124-1.807
C26/C20	1.491↑	0.066-0.716
C24/C22	4.253↑	0.481-3.172
C26/C22	5.307↑	0.183-2.316

A novel mutation in the ABCD1 gene of a patient with X-linked adrenoleukodystrophy presenting with central precocious puberty: a case report

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Abstract

Introduction

Case report

Discussion

Declarations

References

Tables

Status:

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