Low estriol levels in the maternal marker screen as a predictor of X-linked adrenal hypoplasia congenita: Case report

Jasmina Durkovic; Tatjana Milenkovic; Nils Krone; Silvia Parajes; Bojana Mandic

doi:10.2298/sarh1412728d

Low estriol levels in the maternal marker screen as a predictor of X-linked adrenal hypoplasia congenita: Case report

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1412728d ◽

2014 ◽

Vol 142 (11-12) ◽

pp. 728-731 ◽

Cited By ~ 3

Author(s):

Jasmina Durkovic ◽

Tatjana Milenkovic ◽

Nils Krone ◽

Silvia Parajes ◽

Bojana Mandic

Keyword(s):

Adrenal Insufficiency ◽

Failure To Thrive ◽

Severe Hypoglycemia ◽

Maternal Serum ◽

Second Trimester ◽

Adrenal Hypoplasia Congenita ◽

Postnatal Diagnosis ◽

Cheap Method ◽

Adrenal Hypoplasia

Introduction. X-linked adrenal hypoplasia congenita (AHC) is a rare cause of adrenocortical insufficiency. Early postnatal diagnosis may prevent severe hypoglycemia, Addisonian crises and death. Low maternal estriol (E3) levels in the second trimester of pregnancy could indicate the possibility that the fetus suffers from a disorder that causes adrenal insufficiency. Suspicion is based on the fact that E3 originates from dehydroepiandrosterone (DHEA) synthesized in the fetal adrenals. In case of adrenal insufficiency, the impaired production of fetal DHEA leads to a subsequent reduction of E3 concentrations in maternal serum. There are only a few reports of AHC suspected prenatally due to low maternal E3 levels. Case Outline. We describe two brothers with adrenal insufficiency due to AHC. The older brother was admitted to the hospital at the age of 33 days due to failure to thrive, vomiting, and dehydration. Genetic analysis revealed a hemizygous mutation in DAX-1 gene, thus confirming the diagnosis of ACH. The same mutation was detected in his mother. In the second pregnancy, E3 concentrations were determined from maternal serum. Estriol levels during the second trimester were extremely low suggesting the diagnosis of AHC. The diagnosis was confirmed during the neonatal period by genetic testing, and replacement therapy was started at the age of 10 days. This boy never experienced an adverse episode such as hypoglycemia or adrenal crises. Conclusion. Since determination of E3 is a simple, sensitive, noninvasive and cheap method, its use as an obligatory prenatal screening test should be accepted as a standard practice in Serbia.

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A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302012000800006 ◽

2012 ◽

Vol 56 (8) ◽

pp. 496-500 ◽

Cited By ~ 8

Author(s):

Claudilene Battistin ◽

Hamilton Cabral de Menezes Filho ◽

Sorahia Domenice ◽

Mirian Yumie Nishi ◽

Thais Della Manna ◽

...

Keyword(s):

Novel Mutation ◽

Hypogonadotropic Hypogonadism ◽

Failure To Thrive ◽

The Novel ◽

Site Analysis ◽

Adrenal Hypoplasia Congenita ◽

Normal Individuals ◽

Exon 1 ◽

Adrenal Hypoplasia ◽

Low Levels

We report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient. Arq Bras Endocrinol Metab. 2012;56(8):496-500

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Adrenal hypoplasia congenita – an uncommon reason of primary adrenal insufficiency

Annales d Endocrinologie ◽

10.1016/j.ando.2010.04.003 ◽

2010 ◽

Vol 71 (4) ◽

pp. 309-313 ◽

Cited By ~ 4

Author(s):

M. Fichna ◽

M. Żurawek ◽

P. Gut ◽

J. Sowiński ◽

J. Nowak

Keyword(s):

Adrenal Insufficiency ◽

Primary Adrenal Insufficiency ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

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Identification and Analysis of a Novel NR0B1 Mutation in Late-Onset Adrenal Hypoplasia Congenita and Hypogonadism

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa176 ◽

2020 ◽

Vol 5 (2) ◽

Author(s):

Yutaka Hasegawa ◽

Yoshihiko Takahashi ◽

Yuichiro Kezuka ◽

Wataru Obara ◽

Yoichiro Kato ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Missense Mutation ◽

Target Genes ◽

Late Onset ◽

Hypogonadotropic Hypogonadism ◽

Skin Pigmentation ◽

Hydrophobic Core ◽

Testicular Microlithiasis ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

Abstract Objective X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadotropic hypogonadism (HHG) caused by mutations of the NR0B1/DAX1 gene. We aimed to search for the presence of any NR0B1/DAX1 gene mutations in a referred patient and to further characterize the phenotypes of the identified mutation. Case Presentation Herein, we report a Japanese patient with a novel missense mutation of the NR0B1/DAX1 gene resulting in adult-onset AHC and HHG. The patient was referred with diffuse skin pigmentation at 28 years of age, presented partial adrenal insufficiency and had undiagnosed incomplete HHG. Urological examination revealed severe oligospermia and testicular microlithiasis. Results The NR0B1/DAX1 gene mutation was identified by exome sequencing as a novel missense mutation (c.884A>T, p.Leu295His). We conducted in silico modeling of this mutant NR0B1/DAX1 protein (p.Leu295His) which affected the conserved hydrophobic core of the putative ligand-binding domain (LBD). In addition, functional analysis revealed that this mutant showed a decreased ability as a transcriptional repressor to suppress target genes, such as STAR and LHB. Furthermore, this mutant showed functionally impaired repression of steroidogenesis in human adrenocortical H295R cells. Conclusions We identified a novel missense mutation of the NR0B1/DAX1 gene in a patient suffering from late-onset AHC and HHG, who presented with oligospermia and testicular microlithiasis. This mutant NR0B1/DAX1 protein was found to have reduced repressor activity, according to in vitro studies, clinically consistent with the patient’s phenotypic features.

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Adrenal hypoplasia congenita: Delayed presentation of a rare cause of primary adrenal insufficiency

Sri Lanka Journal of Child Health ◽

10.4038/sljch.v47i1.8436 ◽

2018 ◽

Vol 47 (1) ◽

pp. 77

Author(s):

Jyoti Patodia ◽

Mukesh Kumar Gupta

Keyword(s):

Adrenal Insufficiency ◽

Delayed Presentation ◽

Primary Adrenal Insufficiency ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

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Primary Adrenal Insufficiency in a Newborn With Adrenal Hypoplasia Congenita Caused by a Mutation of theDAX1Gene

Neonatal Medicine ◽

10.5385/nm.2016.23.1.53 ◽

2016 ◽

Vol 23 (1) ◽

pp. 53 ◽

Cited By ~ 1

Author(s):

Sun Hyoung Park ◽

Yong Hee Hong ◽

Sung Shin Kim

Keyword(s):

Adrenal Insufficiency ◽

Primary Adrenal Insufficiency ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

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Adrenal Hypoplasia Congenita Presenting as Congenital Adrenal Hyperplasia

Case Reports in Endocrinology ◽

10.1155/2013/393584 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Jennifer L. Flint ◽

Jill D. Jacobson

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Failure To Thrive ◽

Zona Glomerulosa ◽

Normal Male ◽

Adrenal Hyperplasia ◽

Acth Stimulation ◽

Hydroxylase Deficiency ◽

Salt Wasting ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

We report on a patient with genetically confirmed adrenal hypoplasia congenita (AHC) whose presentation and laboratory abnormalities were consistent with the more common condition, congenital adrenal hyperplasia (CAH). The patient presented with failure to thrive and salt wasting. General appearance showed marked hyperpigmentation and normal male genitalia. He displayed mildly elevated 17-hydroxyprogesterone and markedly elevated 11-deoxycortisol levels at baseline and with ACTH stimulation testing. Results were consistent with 11β-hydroxylase deficiency. He required glucocorticoids and high doses of mineralocorticoids. The marked elevation in 11-deoxycortisol directed our clinical reasoning away from a hypoplastic condition and towards a hyperplasic adrenal condition. Sequencing of the DAX1 gene (named for dosage-sensitive sex reversal (DSS) locus and the AHC locus on the X chromosome) revealed a missense mutation. A review of the literature revealed that elevated 11-deoxycortisol levels have been noted in kindreds with DAX1 mutations, but only when measured very early in life. A mouse model has recently been described that displays elevated 11-deoxycorticosterone levels and evidence for hyperplasia of the zona glomerulosa of the adrenal gland. We conclude that DAX1 testing may be considered in patients with laboratory evidence of 11β-hydroxylase deficiency, especially in those with severe salt wasting.

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Adrenal hypoplasia congenita: a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism

Pediatric Reports ◽

10.4081/pr.2015.5936 ◽

2015 ◽

Vol 7 (3) ◽

Cited By ~ 3

Author(s):

Marta Loureiro ◽

Filipa Reis ◽

Brígida Robalo ◽

Carla Pereira ◽

Lurdes Sampaio

Keyword(s):

Adrenal Insufficiency ◽

Replacement Therapy ◽

Hypogonadotropic Hypogonadism ◽

Delayed Puberty ◽

Adrenal Crisis ◽

Testosterone Replacement Therapy ◽

Primary Adrenal Insufficiency ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia ◽

Low Levels

Primary adrenal insufficiency is defined by the impaired synthesis of adrenocortical hormones due to an intrinsic disease of the adrenal cortex. Determining its etiology is crucial to allow adequate long-term management and genetic counseling. We report the case of a male adolescent that presented in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During follow-up, adrenal hypoplasia congenita (AHC) was suspected given his persistently raised adrenocorticotropic hormone levels, with markedly low 17-OH progesterone and androstenedione levels. DNA sequence analysis revealed a mutation in <em>NR0B1</em> gene (c.1292delG), confirming the diagnosis. Delayed puberty and persistent low levels of gonadotropins led to testosterone replacement therapy. X-linked AHC is a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in <em>NR0B1</em> gene. Despite its rarity, AHC should be considered in patients who present with primary adrenal failure, low levels of 17-OH progesterone and hypogonadotropic hypogonadism.

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Hyponatremic Seizures and Adrenal Hypoplasia Congenita in a Neonate with Congenital Diaphragmatic Hernia

Case Reports in Pediatrics ◽

10.1155/2019/4178251 ◽

2019 ◽

Vol 2019 ◽

pp. 1-4

Author(s):

Sourabh Verma ◽

Sheryl Purrier ◽

Emily Breidbart ◽

John G. Pappas ◽

Pradeep V. Mally ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Adrenal Insufficiency ◽

Diaphragmatic Hernia ◽

Neonatal Seizure ◽

Postoperative Phase ◽

Severe Hyponatremia ◽

Genetic Syndrome ◽

Adrenal Hypoplasia Congenita ◽

First Case ◽

Adrenal Hypoplasia

Congenital diaphragmatic hernia (CDH) in neonates may occur as an isolated finding, in association with other anomalies, or as part of a genetic syndrome. We report the first case of an infant with CDH who presented with hyponatremic seizures due to adrenal hypoplasia congenita (AHC). The patient underwent repair of CDH defect. After an uncomplicated postoperative course while on discharge planning, he developed a seizure episode associated with severe hyponatremia and hyperkalemia. Extensive diagnostic workup revealed an NR0B1 gene variant confirming the diagnosis of X-linked AHC. The patient was eventually discharged home on hydrocortisone, fludrocortisone, and salt supplements. There are a few case reports of adrenal insufficiency in neonates with CDH, manifesting with symptoms before and immediately after reparative surgery. Clinical presentation of our patient was unique in manifesting as neonatal seizure secondary to severe hyponatremia after a stable postoperative phase. The patient’s electrolytes and hemodynamic status remained stable before, during, and after surgery for CDH. This case underlines the importance of taking detailed family history and continued vigilance for signs and symptoms of adrenal insufficiency in infants with repaired CDH by pediatricians and intensivists.

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