X-linked congenital adrenal hypoplasia: Report of long clinical follow-up and description of a new complex variant in the NR0B1 gene.

Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype-phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4 months. For 3 years, he did well without treatment. At almost 4 years of age, the disorder was restarted. A long follow-up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on NR0B1 revealed a novel and deleterious deletion-insertion-inversion-deletion complex rearrangement sorted in the 5'-3' direction, which is described as follows: (1) deletion of the intergenic region (between TASL and NR0B1 genes) and 5' region, (2) insertion of a sequence containing 37 bp at the junction of the intergenic region of the TASL gene and a part of exon 1 of the NR0B1 gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, (5) maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end-joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an "information scar," represented herein by the 37 bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.

Single-Exon Deletions of ZNRF3 Exon 2 Cause Congenital Adrenal Hypoplasia.

CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition characterized by the inability of the adrenal cortex to produce sufficient steroid hormones. E3 ubiquitin protein ligase zinc and ring finger 3 (ZNRF3) is a negative regulator of Wnt/ß-catenin signaling. R-spondin 1 (RSPO1) enhances Wnt/ß-catenin signaling via binding and removal of ZNRF3 from the cell surface. OBJECTIVE: This work aimed to explore a novel genetic form of PAI. METHODS: We analyzed 9 patients with childhood-onset PAI of biochemically and genetically unknown etiology using array comparative genomic hybridization. To examine the functionality of the identified single-exon deletions of ZNRF3 exon 2, we performed three-dimensional (3D) structure modeling and in vitro functional studies. RESULTS: We identified various-sized single-exon deletions encompassing ZNRF3 exon 2 in 3 patients who showed neonatal-onset adrenal hypoplasia with glucocorticoid and mineralocorticoid deficiencies. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that the 3 distinct single-exon deletions were commonly transcribed into a 126-nucleotide deleted mRNA and translated into 42-amino acid deleted protein (ΔEx2-ZNRF3). Based on 3D structure modeling, we predicted that interaction between ZNRF3 and RSPO1 would be disturbed in ΔEx2-ZNRF3, suggesting loss of RSPO1-dependent activation of Wnt/ß-catenin signaling. Cell-based functional assays with the TCF-LEF reporter showed that RSPO1-dependent activation of Wnt/ß-catenin signaling was attenuated in cells expressing ΔEx2-ZNRF3 as compared with those expressing wild-type ZNRF3. CONCLUSION: We provided genetic evidence linking deletions encompassing ZNRF3 exon 2 and congenital adrenal hypoplasia, which might be related to constitutive inactivation of Wnt/ß-catenin signaling by ΔEx2-ZNRF3.

A Case of X-Linked Adrenal Hypoplasia Congenital (AHC) Due to Large Deletion of NR0B1 (DAX1) and Contiguous Gene.

X-linked adrenal hypoplasia congenita (AHC) is caused predominantly by mutations in the NR0B1 (DAX1) gene. Among these, X-linked AHC due to a large deletion of NR0B1 is extremely rare. In Korea, the first case was reported in 2005, and there have been no further documented cases since then. Herein, we report a unique case of X-linked AHC caused by an entire gene deletion that includes the NR0B1 gene and seven other genes. A seven-day-old boy presented to a pediatric endocrine clinic with prolonged postnatal jaundice, skin hyperpigmentation, hyponatremia, and hyperkalemia, suggestive of an adrenal crisis. In genetic analysis, next-generation sequencing panel for congenital adrenal hyperplasia (CAH) showed no variants. However, chromosomal microarray results revealed large deletion of Xp21.2 (29,655,007_30,765,126) including eight protein-coding genes (NR0B1, IL1RAPL1, GK, MAGEB1-4, TASL). In cases of atypical adrenal insufficiency and genetically undiagnosed CAH, NR0B1-related AHC should be suspected, as Xp21 deletion is very rare and not detected in NGS, making microarray the best option for genetic diagnosis.

Clinical and genetic characteristics of 42 Chinese paediatric patients with X-linked adrenal hypoplasia congenita.

BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization. METHODS: The clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed. RESULTS: Hyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year. CONCLUSIONS: This study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.

Xp21 contiguous gene deletion syndrome presenting as Duchenne muscular dystrophy and glycerol kinase deficiency associated with intellectual disability: case report and review literature.

The contiguous gene deletion syndromes (CGDS) are rare genomic disorders resulting from the deletion of large segments of DNA, manifested as the concurrence of apparently unrelated clinical features. A typical example of CGDS is Xp21 contiguous gene deletion syndrome that involves GK and its neigh-boring genes (usually DMD and NR0B1) and results in a complex phenotype, which is related to the size of deletion and involved genes. Development delay and intellectual disability are almost a constant feature of patients with CGDS. We report the case of a boy with Duchenne muscular dystrophy (DMD) and glycerol kinase deficiency (GKD) as part of the contiguous gene deletion syndrome Xp2.1, in association with intellectual disability (ID) in whom multiplex ligation-dependent probe amplification (MLPA) test first identified a hemizygous deletion involving the entire dystrophin gene. Subsequently, the array CGH study identified a maternally inherited hemizygous deletion of the Xp21.2-Xp21.1 region of approximately 3.7Mb that included both DMD and GK genes confirming the diagnosis of Xp21 CGDS. Moreover, we report a review of the cases published in the literature over the last 20 years, for which a better description of the genes involved in the syndrome was available. Intellectual disability does not appear as a constant feature of the syndrome, reiterating the concept that complex GKD syndrome results from small deletions that affect closely related but separate loci for DMD, GK and adrenal hypoplasia, rather than a single large deletion including all genes. This case highlights the importance of more in-depth genetic investigations in presence of apparently unrelated clinical findings, allowing an accurate diagnosis of contiguous gene deletion syndromes.

New insights into X-linked adrenal hypoplasia congenita from a novel splice-site variant of NR0B1 and adrenal CT images.

BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder, often manifesting as primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), and caused by variants of NR0B1, most of which are frame-shifting variants, and few splice-site variants. METHODS AND RESULTS: Here, a novel splice-site variant of NR0B1 (NM_000475.4), c.1169-2A>T (patient 1), and a stop-loss variant of NR0B1 c.1411T>C (patient 2) are described in this study. We perform minigene assays for the splice-site variant (c.1169-2A>T) and determine that the variant causes exon 2 skipping. Moreover, the defect of NR0B1 protein may bring about the severe phenotype of the patient. Through 8 years of follow-up, we compare the CT images from 8 years ago with the latest image, and observe the CT image change of adrenal in patient 2 (from the increased thickness of adrenal to adrenal atrophy). CONCLUSION: X-linked adrenal hypoplasia congenita is produced by variants of NR0B1. We report a case that presents a novel splice-site variant, which has been verified that it could lead to the exon 2 skipping in the RNA splicing progress. Moreover, we report the adrenal CT image change of patient 2, which has never been referred to before, and expand the spectrum of X-linked AHC characteristics.

Novel non-stop variant of the NR0B1 gene in two siblings with adrenal hypoplasia congenita.

OBJECTIVES: Mutations in the dosage-sensitive sex reversal-AHC critical region on the X chromosome, gene 1 (DAX-1, officially NR0B1), cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). Salt-losing adrenal insufficiency usually occurs during the neonatal period or early childhood. We report a novel non-stop variant of NR0B1 in two siblings and their unusual clinical course. CASE PRESENTATION: The proband was a boy who presented with an unusual form of AHC with neonatal onset of growth failure and mild salt loss, but without cutaneous pigmentation or plasma ACTH elevation. His 4-year-old elder brother had been growing healthily, but carried an AHC diagnosis. A non-stop variant of NR0B1 (p.*471K) was demonstrated in the patients and their mother. CONCLUSIONS: We identified a novel non-stop variant of NR0B1 in two siblings. Mild salt loss associated with hyperkalemia is a crucial diagnostic clue for AHC, even without apparent symptoms of glucocorticoid deficiency.

Case Report: A Novel Truncating Variant of NR0B1 Presented With X-Linked Late-Onset Adrenal Hypoplasia Congenita With Hypogonadotropic Hypogonadism.

Nuclear receptor subfamily 0 group B member 1 gene (NR0B1) encodes an orphan nuclear receptor that plays a critical role in the development and regulation of the adrenal gland and hypothalamic-pituitary-gonadal axis. In this study, we report a novel mutation in NR0B1 that led to adult-onset adrenal hypoplasia congenita (AHC) and pubertal development failure in a male adult. Clinical examinations revealed hyponatremia, elevated adrenocorticotropic hormone levels, reduced testosterone and gonadotropin levels, and hyper-responses to gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests. Whole-exome sequencing and Sanger sequencing were performed to identify the potential causes of AHC. Candidate variants were shortlisted based on the X-linked recessive models. Sequence analyses identified a novel hemizygous variant of c.1034delC in exon 1 of NR0B1 at Xp21.2, resulting in a frameshift mutation and premature stop codon formation. The c.1034delC/p.Pro345Argfs*27 in the NR0B1 gene was detected in the hemizygous state in affected males and in the heterozygous state in healthy female family carriers. These results expand the clinical features of AHC as well as the mutation profile of the causative gene NR0B1. Further studies are needed to elucidate the biological effects of the mutation on the development and function of the adrenal gland and the hypothalamic-pituitary-gonadal axis.

Pleomorphism of the HPG axis with NR0B1 gene mutation - a case report of longitudinal follow-up of a proband with central precocious puberty.

OBJECTIVES: X-linked adrenal hypoplasia congenita (AHC) is characterized by adrenal insufficiency and hypogonadotropic hypogonadism. Herein, we report a rare case of X-linked AHC with central precocious puberty (CPP). CASE PRESENTATION: An 11-month-old male patient was found to have premature pubarche, enlargement of the penis, and frequent erection. LH and FSH levels after the GnRHa test were in the pubertal range. Direct sequencing revealed a heterozygous variant of the NR0B1 gene. The proband was treated with hydrocortisone and 9-alpha fludrocortisone because of the significantly elevated ACTH and renin activity. The secondary sexual characteristics relieved gradually. The serum testosterone and LH subsequently returned to the prepubertal range. The basal serum FSH values have been between 1.0 and 2.0 IU/L since the age of 2.25 years, with extremely low AMH levels beginning at 3 years. CONCLUSIONS: The clinical course of CPP with NR0B1 variant may be temporary. HPG axis status of X-linked AHC may probably be pleomorphic during the longitudinal follow-up.

[A Novel Pathogenic variant in NR0B1 gene associated with Congenital Adrenal Hypoplasia]. / Nueva Variante Patogénica en el Gen NR0B1 Asociada a Hipoplasia Adrenal Congénita.

X-linked adrenal hypoplasia congenita is a rare cause of primary adrenal insufficiency. Mutations in the NR0B1 gene cause a loss of function in the DAX1 receptor, which activates genes involved in the development and function of the hypothalamic-pituitary-gonadal axis. Objective: To describe a case of adrenal hypoplasia congenita secondary to a mutation in the NR0B1 gene and identified the differential diagnoses of the pediatric patient with adrenal insufficiency and hypogonadotropic hypogonadism. Clinical Case: A 4-year-old male patient with no relevant history and from a rural area was admitted to the emergency room due to a 15-days of emesis, asthenia, adynamia, myalgia, and ataxic gait. On the physical examination, hypotension, hyponatremia, and hyperkalemia, as well as mucosal hyperpigmentation and bilateral cryptorchidism were observed, therefore, adrenal crisis was diagnosed, starting fluid resuscitation with saline solution, hydrocortisone, and fludrocortisone, which stabilized the patient. Adrenal hyperplasia congenita, innate metabolic error, and infectious or autoimmune etiology were ruled out as etiology. A clinical exome test was performed which iden tified the variant c.1275A > T; p.Arg425Ser (Transcript ENST00000378970.5) in the NR0B1 gene consistent with X-linked adrenal hypoplasia congenita. Management of the patient continued with glucocorticoids and mineralocorticoids with favorable clinical course at 7 years of follow-up. Con clusion: A novel pathogenic variant associated with X-linked adrenal hypoplasia is described. Variants in the NR0B1 gene should be a differential diagnosis in a male patient with the association of primary adrenal insufficiency and hypogonadism.

X-linked congenital adrenal hypoplasia: a case presentation.

BACKGROUND: Most patients with congenital adrenal hypoplasia (AHC) develop symptoms during infantile and juvenile periods, with varying clinical manifestations. AHC is a disease that is easily misdiagnosed as Addison's disease or congenital adrenal hyperplasia (CAH). There was also a significant time difference between the age at which patients developed symptoms and the age at which they were diagnosed with AHC. Most patients showed early symptoms during infantile and juvenile periods, but were diagnosed with AHC many years later. CASE PRESENTATION: We are currently reporting a male patient who developed systemic pigmentation at age 2 and was initially diagnosed with Addison's disease. At 22 years of age, he experienced a slipped capital femoral epiphysis (SCFE), a disease mostly seen in adolescents aged 8-15 years, an important cause of which is endocrine disorder. Testes evaluated using color Doppler Ultrasonography suggested microcalcifications. Further genetic testing and auxiliary examinations revealed that the patient had hypogonadotropic hypogonadism (HH) and DAX-1 gene disorders, at which time he was diagnosed with AHC complicated by HH. He was given hormone replacement therapy, followed by regular outpatient review to adjust the medication. CONCLUSIONS: The typical early symptoms of AHC are hyperpigmentation and ion disturbance during infantile and juvenile periods, while few patients with AHC develop puberty disorders as early symptoms. AHC is prone to being misdiagnosed as Addison's disease, and then gradually develops the symptoms of HH in adolescence. The definitive diagnosis of AHC ultimately is based on the patient's clinical presentation, laboratory results and genetic testing results.

A novel stop-loss DAX1 variant affecting its protein-interaction with SF1 precedes the adrenal hypoplasia congenital with rare spontaneous precocious puberty and elevated hypothalamic-pituitary-gonadal/adrenal axis responses.

The case study unveils the likely mechanism of a novel stop-loss DAX1 variant preceding the prolonged precocious puberty in the adrenal hypoplasia congenital (AHC) boy. A boy aged five years and nine months initially examined for the primary adrenal insufficiency symptoms. Next-generation sequencing confirmed the X-linked inheritance of a novel stop-loss DAX1 variant: c.1411T>C/p.Ter471Gln associated with AHC in the patient. The patient was subjected to a brief clinical follow-up from 11 to 15.1 years of age. The effect of the mutant-DAX1 variant (p.Ter471Gln) on DAX1-steroidogenic factor 1 (SF1) (protein-protein) interaction was studied by protein-protein docking using the ClusPro-online tool. At 5.9 yrs of age, the patient exhibited precocious puberty with the secondary sexual characteristics of Tanner 2 stage (of 9-14 yrs of age). The patient showed primary adrenal insufficiency with diminished cortisol concentrations at blood serum (25 ng/ml) and urine (3.55 µg/24 h) levels. Upon steroidal exposure, the patient showed normalized serum cortisol levels of 45-61 ng/ml. However, the precocious puberty got prolonged with the increased penis length of 8.5 cm and the bone age of 18 yrs old during the follow-up. The patient showed increased basal serum adrenocorticotropic hormone (110->2000 pg/ml) and follicle-stimulating hormone (18.4-22.3 mIU/ml) concentrations. Following an elevated hypothalamic-pituitary-gonadal axis activity witnessed upon gonarellin stimulation. Protein-protein docking confirmed a weaker interaction between the mutant-DAX1 (p.Ter471Gln) protein and the wild-SF1 protein. Overall, we hypothesize the weakened mutant-DAX1-SF1 (protein-protein) interaction could govern the prolonged precocious puberty augmented with the elevated hypothalamic-pituitary-gonadal/adrenal axis responses via SF1-induced neuronal nitric oxide synthetase activation in the patient.

A girl with MIRAGE syndrome who developed steroid-resistant nephrotic syndrome: a case report.

BACKGROUND: MIRAGE syndrome is a recently discovered rare genetic disease characterized by myelodysplasia (M), infection (I), growth restriction (R), adrenal hypoplasia (A), genital phenotypes (G), and enteropathy (E), caused by a gain-of-function mutation in the SAMD9 gene. We encountered a girl with molecularly-confirmed MIRAGE syndrome who developed steroid-resistant nephrotic syndrome. CASE PRESENTATION: She was born at 33 weeks gestational age with a birth weight of 1064 g. She showed growth failure, mild developmental delays, intractable enteropathy and recurrent pneumonia. She was diagnosed as MIRAGE syndrome by whole exome sequencing and a novel SAMD9 variant (c.4615 T > A, p.Leu1539Ile) was identified at age four. Biopsied skin fibroblast cells showed changes in the endosome system that are characteristic of MIRAGE syndrome, supporting the genetic diagnosis. Proteinuria was noted at age one, following nephrotic syndrome at age five. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) with immune deposits. Steroid treatment was ineffective. Because we speculated that her nephrosis was a result of genetic FSGS, we decided not to introduce immunosuppressive agents and instead started enalapril to reduce proteinuria. Although her proteinuria persisted, her renal function was normal at age eight. CONCLUSIONS: This is the first detailed report of a MIRAGE syndrome patient with nephrotic syndrome. Because patients with MIRAGE syndrome have structural abnormalities in the endosomal system, we speculate that dysfunction of endocytosis in podocytes might be a possible mechanism for proteinuria.

Report: central diabetes insipidus and schwannoma in a male with X-linked congenital adrenal hypoplasia.

BACKGROUND: DAX1 mutations are related to the X-linked form of adrenal hypoplasia congenita (AHC) in infancy and to hypogonadotropic hypogonadism (HH) in puberty. We report a male patient affected by X-linked AHC who presented with central diabetes insipidus and schwannoma in adulthood, which has not been described in association with AHC. CASE PRESENTATION: A 36-day-old male infant who presented with severe dehydration was admitted to the intensive care unit. His laboratory findings showed hyponatremia, hyperkalemia, hypoglycemia, and metabolic acidosis. After hormonal evaluation, he was diagnosed with adrenal insufficiency, and he recovered after treatment with hydrocortisone and a mineralocorticoid. He continued to take hydrocortisone and the mineralocorticoid after discharge. At the age of 17, he did not show any signs of puberty. On the basis of a GnRH test, a diagnosis of HH was made. At the age of 24, he was hospitalized with thirst, polydipsia and polyuria. He underwent a water deprivation test for polydipsia and was diagnosed with central diabetes insipidus. By quantitative polymerase chain reaction analysis, we identified a hemizygous frameshift mutation in DAX1 (c.543delA). CONCLUSIONS: We suggest that DAX1 mutations affect a wider variety of endocrine organs than previously known, including the posterior pituitary gland.

A Novel NR0B1 Gene Mutation Causes Different Phenotypes in Two Male Patients with Congenital Adrenal Hypoplasia.

X-linked congenital adrenal hypoplasia is characterised by the acute onset of primary adrenal insufficiency in infancy or early childhood and hypogonadotropic hypogonadism (HH) at puberty, arising from mutations of the nuclear receptor subfamily 0 group B member 1 (NR0B1) gene. This study investigated an extended family with two affected males (patient A: 23 years and patient B: 2 months old) and three carrier females. Sequencing analysis of the NR0B1 gene coding region from the family revealed a novel hemizygous deletion [c.604delT; p.(C202Afs*62)] in the two male patients. Furthermore, the patients' respective mothers and their common grandmother had this heterozygous mutation, but it was not present in the Human Gene Mutation Database. The two male patients showed inconsistent clinical features at onset, particularly in early childhood; however, it is possible that the younger patient will eventually show a delay of puberty, feminisation, and nonspermatogenesis in adulthood, similar to that in the older patient. Identification of a novel NR0B1 mutation in this family is important for the diagnosis and genetic counselling of children with primary adrenal insufficiency and HH, and will be helpful for predicting long-term clinical symptoms.

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children.

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

Novel frameshift mutation of the NR0B1(DAX1) in two tall adult brothers.

NR0B1 (nuclear receptor subfamily 0, group B, member 1) is a transcription factor encoded by DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) responsible for the development and maintenance of the steroidogenic tissues. In humans the DAX1 mutations cause congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism (HHG) in boys. Here we report two brothers who were assessed by endocrinologist at the age of 51 and 43 because of their serious osteoporosis. They had been substituted with prednisolone since the age of 4 and 9 years because of their primary adrenal insufficiency (PAI). Due to their late puberty caused by HHG at the age of 16 and 17 years their heights were - 3.1 and - 3.3 SD, but then they had a significant growth during their adulthood and reached the + 1.85 SD and + 3.78 SD respectively. During this period, they received glucocorticoid supplementation, but the treatment of their HHG was inadequate. At the age of 51 and 43 years insulin tolerance test (ITT) and gonadotropin releasing hormone (GnRH) test confirmed their PAI and HHG. Genetic test performed at this time revealed a novel, four nucleotides deletion (del.586-571c.GGGC or 572-575c.GGGC) of DAX1 gene. The two brothers with AHC and HHG caused by a novel DAX1 mutation, reached tall final heights, despite of the disadvantageous prednisolone treatment during their childhood. We assume that the long-term lack of the sexual hormone substitution was a significant reason of their above average height as well as their serious osteoporosis.

Isolated hypoaldosteronism as first sign of X-linked adrenal hypoplasia congenita caused by a novel mutation in NR0B1/DAX-1 gene: a case report.

BACKGROUND: X-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1. Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease. CASE PRESENTATION: A 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC. CONCLUSIONS: AHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.

[A four-generation pedigree affected with X-linked adrenal hypoplasia congenita due to a novel missense DAX1 mutation].

OBJECTIVE: To report on the clinical pictures of 7 patients from a pedigree affected with X-linked adrenal hypoplasia congenita (XL-AHC) and hypogonadotropic hypogonadism (HH) and the underlying mutations. METHODS: Seven patients were identified from a four-generation pedigree affected with XL-AHC and HH. Their clinical features, endocrinological changes, treatment and drug response were recorded. The patients were subjected to next-generation sequencing, and the result was verified by Sanger sequencing. PolyPhen-2 was used for predicting the influence of the mutation on protein production. RESULTS: Three deceased patients had manifested adrenal insufficiency (AI) within one year after birth. Two died at 6 and one died at 12. The four survivors presented with salient clinical and endocrinological features of AHC and HH, adrenal and testicular atrophy, and renin-angiotensin compensation. Two adult patients had testicular micro-stone detected by ultrasound.One of them also had remarkable seminiferous tubule degeneration by biopsy. The patients were followed up for 0.5 to 10 years. All required hyper-physiological dose of hydrocortisone to stabilize their clinical condition. In three patients, gonadotropic or androgen replacement induced cardinal masculine development but with unsatisfactory testis growth and sperm production.Genetic analysis revealed a novel missense c.827A>C (p.Q276P) mutation in a hotspot region within a highly conserved domain. PolyPhen-2 predicted the mutation to be highly hazardous. CONCLUSION: The novel p.Q276P mutation of the DAX1 gene probably underlies the XL-AHC and HH in this pedigree with variable clinical presentations in the patients.

Hipoplasia adrenal congénita ligada al cromosoma X: mutación missense de novo en el gen DAX-1 / X-linked adrenal hypoplasia congenita: Novel missense mutation of DAX-1 gene

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