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John C Achermann

Publications and source records attributed to John C Achermann.

At least 19 recordsLinked to original sources
PubMed2026

Clinical, Histopathological, and Molecular Characterization of Pediatric MN1::ZNF341-Associated Cancer.

A lethal round-cell malignancy with an MN1::ZNF341 fusion has recently been reported in three infants. Here, we describe four further tumors, three in newborns (including monozygotic twins), and one in an adolescent. Detailed clinical, radiological, and histopathological data differentiate these tumors from their main mimics, neuroblastoma and round-cell sarcomas. Single-cell RNA sequencing confirms the tumor to be transcriptionally distinct from neuroblastoma, instead exhibiting steroidogenic differentiation. Whole genome and targeted DNA sequencing yield no further driver events. Our work reveals a broader clinicopathological phenotype than previously appreciated and corroborates suggestions that this tumor is a distinct and aggressive childhood cancer.

Humans↗
PubMed2007

Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.

CONTEXT: Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure. OBJECTIVE: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY disorders of sex development) with normal adrenal function. METHODS AND PATIENTS: The study included mutational analysis of NR5A1 in 30 individuals with 46,XY disorders of sex development, followed by functional studies of SF1 activity. RESULTS: Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered subnuclear localization (V15M, M78I), or disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change. CONCLUSIONS: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals.

Adolescent↗
PubMed2007

Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia.

OBJECTIVE: Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. DESIGN: Mutational analysis of MC2R by direct sequencing. PATIENTS: Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). RESULTS: MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. CONCLUSIONS: MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosis.

Adrenal Insufficiency↗
PubMed2006

Variable phenotypes associated with aromatase (CYP19) insufficiency in humans.

CONTEXT: The P450 enzyme aromatase (CYP19) plays a crucial role in the endocrine and paracrine biosynthesis of estrogens from androgens in many diverse estrogen-responsive tissues. Complete aromatase deficiency has been reported in a small number of 46,XX girls with genital ambiguity and absent pubertal development, but it is unknown whether nonclassic phenotypes exist. OBJECTIVE: The objective of this study was to determine whether variant forms of aromatase insufficiency can occur in humans. PATIENTS AND METHODS: Four patients (46,XX) from three kindreds with variable degrees of androgenization and pubertal failure were studied using mutational analysis of CYP19 and assay of enzyme activity. RESULTS: Aromatase insufficiency resulting in genital ambiguity at birth, but with variable breast development at puberty (B2-B4), occurred in 46,XX patients from two kindreds who harbored point mutations or single codon deletions (R435C, F234del). Absent puberty with minimal androgenization at birth was found in one girl with a deletion involving exon 5 of CYP19 (exon5del), which would be predicted to lead to an in-frame deletion of 59 amino acids from the enzyme. Functional studies revealed low residual aromatase activity in the cases in which breast development occurred. CONCLUSIONS: These studies demonstrate that aromatase mutations can produce variable or "nonclassic" phenotypes in humans. Low residual aromatase activity may be sufficient for breast and uterine development to occur at puberty, despite significant androgenization in utero. Such phenotypic variability may be influenced further by modifying factors such as nonclassic pathways of estrogen synthesis, variability in coregulators, or differences in androgen responsiveness.

Adolescent↗
PubMed2006

A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia.

CONTEXT: The GnRH receptor plays a central role in regulating gonadotropin synthesis and release, and several mutations in the GNRHR gene have been reported in patients with idiopathic or familial forms of isolated hypogonadotropic hypogonadism (IHH). OBJECTIVE: The objective of the study was to investigate whether partial loss-of-function mutations in the GnRH receptor might be responsible for delayed puberty phenotypes. PATIENTS: Patients included sibling pairs with delayed puberty (n = 8) or those in whom one brother had delayed puberty and another had hypogonadotropic hypogonadism (n = 3). METHODS: Methods included mutational analysis of the GNRHR gene. RESULTS: A homozygous R262Q mutation in the GnRH receptor was identified in two brothers from one family. In this kindred, the proband presented at 15 yr of age with delayed puberty. After a short course of testosterone, he seemed to be progressing through puberty appropriately and was discharged from follow-up. His younger brother was also referred with delayed puberty but showed little progress after treatment. Frequent sampling revealed detectable but apulsatile LH and FSH release. His clinical progress was consistent with IHH, and he requires ongoing testosterone replacement. CONCLUSIONS: Homozygous partial loss-of-function mutations in the GnRH receptor, such as R262Q, can present with variable phenotypes including apparent delayed puberty. Ongoing clinical vigilance might be required when patients are discharged from follow-up, especially when there is a family history of delayed puberty or IHH because oligospermia and reduced bone mineralization can occur with time.

Adolescent↗
PubMed2006

Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia.

CONTEXT: Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis, and 46,XY genetic males have complete lack of androgenization and appear phenotypically female due to impaired testicular androgen secretion in utero. OBJECTIVE: The objective of this study was to investigate whether nonclassic forms of this condition exist. PATIENTS AND METHODS: Sequence analysis of the gene encoding StAR was undertaken in three children from two families who presented with primary adrenal insufficiency at 2-4 yr of age; the males had normal genital development. Identified mutants were tested in a series of biochemical assays. RESULTS: DNA sequencing identified homozygous StAR mutations Val187Met and Arg188Cys in these two families. Functional studies of StAR activity in cells and in vitro and cholesterol-binding assays showed these mutants retained approximately 20% of wild-type activity. CONCLUSIONS: These patients define a new disorder, nonclassic lipoid congenital adrenal hyperplasia, and represent a new cause of nonautoimmune Addison disease (primary adrenal failure).

Addison Disease↗
PubMed2006

Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.

The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice.

Abnormalities, Multiple↗
PubMed2006

Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience.

CONTEXT: Primary adrenal failure is a life-threatening condition that can be caused by a range of etiologies, including autoimmune, metabolic, and developmental disorders. The nuclear receptors DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) play an important role in adrenal development and function, and mutations in these transcription factors have been found in patients with adrenal hypoplasia. OBJECTIVE: Our objective was to investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e. not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). PATIENTS: One hundred seventeen patients were included. Eighty-eight individuals presented in infancy or childhood with adrenal hypoplasia or primary adrenal failure of unknown etiology (n = 64 46,XY phenotypic males; n = 17 46,XY gonadal dysgenesis/impaired androgenization; n = 7 46,XX females). Twenty-nine individuals presented in adulthood with Addison's disease of unknown etiology. METHODS: Mutational analysis of DAX1 (NR0B1) (including exon 2alpha/1A) and SF1 (NR5A1) was done by direct sequencing. RESULTS: DAX1 mutations were found in 58% (37 of 64) of 46,XY phenotypic boys referred with adrenal hypoplasia and in all boys (eight of eight) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found in only two patients with 46,XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group. CONCLUSIONS: DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.

Adolescent↗
PubMed2006

IMAGe association and congenital adrenal hypoplasia: no disease-causing mutations found in the ACD gene.

The spontaneous mouse mutant adrenocortical dysplasia (acd) is characterized by defects in the adrenals, kidneys, and gonads of adult mutant mice and by caudal dysgenesis and vertebral segmentation defects in acd embryos. This association of defects mirrors those identified in patients with known or suspected abnormalities in adrenocortical development, including adrenal hypoplasia congenita and IMAGe association. The identification of the Acd gene in mice has prompted the study of its human homolog ACD, which has recently been shown to be a regulator of telomere length. Sequencing of ACD in 15 patients revealed no coding mutations, but three novel SNPs were identified.

Adrenal Insufficiency↗
PubMed2006

Steroidogenic factor-1 (SF-1) and its relevance to pediatric endocrinology.

Steroidogenic factor-1 (SF-1) (NR5A1) is a member of the nuclear receptor superfamily that is expressed widely throughout the adrenal and reproductive axes during development and plays a central role in the function of these endocrine systems in post-natal and adult life. Much has been learned about the role of this transcription factor since its initial cloning in 1992, largely due to the creation of an Sf-1 (FtzF1) knockout mouse model, in vitro studies of nuclear receptor function and, more recently, following identification and characterization of patients with naturally-occurring SF-1 mutations. In this review, we will summarize how our knowledge of SF-1 in endocrine development and disease evolved to its current state, focusing on the spectrum of phenotypes associated with mutations in this transcription factor in patients who might present to a pediatric endocrinologist.

Animals↗
PubMed2005

A novel mutation L260P of the steroidogenic acute regulatory protein gene in three unrelated patients of Swiss ancestry with congenital lipoid adrenal hyperplasia.

CONTEXT: Lipoid congenital adrenal hyperplasia (CAH) is the most severe form of CAH leading to impaired production of all adrenal and gonadal steroids. Mutations in the gene encoding steroidogenic acute regulatory protein (StAR) cause lipoid CAH. OBJECTIVE: We investigated three unrelated patients of Swiss ancestry who all carried novel mutations in the StAR gene. All three subjects were phenotypic females with absent Müllerian derivatives, 46,XY karyotype, and presented with adrenal failure. METHODS AND RESULTS: StAR gene analysis showed that one patient was homozygous and the other two were heterozygous for the novel missense mutation L260P. Of the heterozygote patients, one carried the novel missense mutation L157P and one had a novel frameshift mutation (629-630delCT) on the second allele. The functional ability of all three StAR mutations to promote pregnenolone production was severely attenuated in COS-1 cells transfected with the cholesterol side-chain cleavage system and mutant vs. wild-type StAR expression vectors. CONCLUSIONS: These cases highlight the importance of StAR-dependent steroidogenesis during fetal development and early infancy; expand the geographic distribution of this condition; and finally establish a new, prevalent StAR mutation (L260P) for the Swiss population.

Adrenal Hyperplasia, Congenital↗
PubMed2005

Isolated 17,20-lyase (desmolase) deficiency in a 46,XX female presenting with delayed puberty.

OBJECTIVE: To investigate the cause of hypergonadotropic hypogonadism. DESIGN: Case report and literature review. SETTING: University Departments of Pediatric Endocrinology and Obstetrics and Gynecology. PATIENT(S): A 13.5-year-old girl with absent puberty and growth retardation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Detailed biochemical, radiological, and molecular analysis, including pelvic ultrasound, basal steroid hormone analysis in serum and aspirated follicle fluid, serum steroid measurement after ACTH (Synachten) and human chorionic gonadotropin (hCG) stimulation, and molecular analysis of CYP17. RESULT(S): This girl with hypergonadotropic hypogonadism (LH 65 U/L, FSH 50 U/L) had a 46,XX karyotype, small uterus and enlarged cystic ovaries, and markedly delayed bone age (9 years). Basal (serum, follicular) and stimulated (serum) steroid hormone levels were consistent with isolated 17,20-lyase deficiency whereas relatively normal P and 17-hydroxyprogesterone concentrations were detected together with very low androstenedione, T, and E(2) levels. CONCLUSION(S): Isolated 17,20-lyase deficiency should be considered in the differential diagnosis of hypergonadotropic hypogonadism in 46,XX females, and follicular fluid steroid analysis is a useful adjuvant test. Failure to detect mutations in CYP17 raises the possibility of a novel association of these phenotypes.

Adolescent↗
PubMed2004

Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure.

Disruption of the P450 side-chain cleavage cytochrome (P450scc) enzyme due to deleterious mutations of the CYP11A1 gene is thought to be incompatible with fetal survival because of impaired progesterone production by the fetoplacental unit. We present a 46,XY patient with a homozygous disruption of CYP11A1. The child was born prematurely with complete sex reversal and severe adrenal insufficiency. Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single nucleotide deletion leading to a premature termination at codon position 288. This mutation will delete highly conserved regions of the P450scc enzyme and thus is predicted to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation. Our report demonstrates that severe disruption of P450scc can be compatible with survival in rare instances. Furthermore, defects in this enzyme are inherited in an autosomal-recessive fashion, and heterozygote carriers can be healthy and fertile. The possibility of P450scc-independent pathways of steroid synthesis in addition to the current concept of luteoplacental shift of progesterone synthesis in humans has to be questioned.

Adrenal Insufficiency↗
PubMed2004

The adrenal.

During the past 15 years, considerable progress has been made in our understanding of the genetic basis of adrenal development and function. More than 30 single gene disorders have now been identified that can affect the hypothalamic-pituitary-adrenal axis in humans (fig. 1, 2; table 1). This review highlights recent advances in the molecular pathology of: (1) adrenal hypoplasia, (2) adrenal destruction, (3) disorders of adrenal steroidogenesis, (4) adrenal steroid resistance and (5) activation of the adrenal axis/tumorigenesis. Characterizing the molecular basis and natural history of these conditions is providing fascinating insight into adrenal development and function and can help to focus treatment and counselling of patients appropriately. However, ongoing translation of research findings into clinical practice is needed if patient care is to be influenced significantly.

Addison Disease↗
PubMed2003

A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics.

BACKGROUND: Inactivating mutations of the FSH receptor (FSHR) are a rare cause of hypergonadotrophic hypogonadism in women. Only one patient with primary amenorrhoea due to an FSHR gene mutation has been reported outside of Finland, where the prevalence of Ala189Val mutations is particularly high. METHODS AND RESULTS: Here, we describe the clinical, molecular genetic and functional characteristics associated with a novel inactivating mutation in exon 10 of the FSHR gene identified in a patient who presented with primary amenorrhoea at 17 years of age. The C to G transversion found at nucleotide 1043 causes a Pro348Arg substitution in the extracellular region of the FSHR and results in a mutant FSHR that is completely inactive in functional studies and that does not bind FSH. The proband exhibits apparent homozygosity for this recessive mutation. Her father is heterozygous for the mutation while analysis of exon 10 of the FSHR gene from her mother revealed only wild-type sequence. Chromosome painting was used to exclude deletions or rearrangements of 2p, and microsatellite markers did not show paternal uniparental isodisomy for this region. These findings suggest that the proband is hemizygous, with an inherited or de-novo microdeletion, or alternatively a de-novo gene conversion, of the accompanying FSHR allele. CONCLUSIONS: This case confirms the importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations.

Adolescent↗
PubMed2003

SF1 in the development of the adrenal gland and gonads.

SF1 (steroidogenic factor-1; NR5A1) is an orphan nuclear receptor that is expressed in the adrenal gland, gonads, spleen, ventromedial hypothalamus and pituitary gonadotroph cells. Combined approaches of targeted mutagenesis in mice and examination of the effects of naturally occurring mutations in humans have clarified the role of SF1 in steroidogenesis and development. Targeted disruption of SF1 (FTZF1) in mice prevents gonadal and adrenal development and causes male-to-female sex reversal. A heterozygous loss-of-function human SF1 mutation (G35E) was described in a patient with adrenal failure and complete 46,XY sex reversal, indicating that haploinsufficiency of this transcription factor is sufficient to cause a severe clinical phenotype. In an infant with a similar clinical phenotype, a homozygous SF1 mutation (R92Q) was identified. In functional assays, this mutant SF1 protein exhibited partial loss of DNA binding and transcriptional activity when compared with the more severe G35E P-box mutant. These patients reveal the exquisite sensitivity of SF1-dependent developmental pathways to gene dosage and function in humans.

Adrenal Glands↗
PubMed2003

An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita.

Mutations in DAX1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome gene 1; NR0B1] cause X-linked AHC, a disease characterized by primary adrenal failure in infancy or childhood and reproductive abnormalities later in life. Most of these patients have nonsense or frameshift mutations that cause premature truncation of the DAX1 protein, thereby eliminating its transcriptional silencing activity. We evaluated a patient with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure. DNA sequence analysis revealed a novel amino-terminal DAX1 nonsense mutation (Q37X), predicted to cause a severe truncation of the protein. Using a combination of in vitro translation assays and studies of DAX1 expression and function in transfected cells, we demonstrate that, in contrast to more distal mutations leading to a nonfunctional protein, this mutation is associated with a milder phenotype due to the expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine, codon 83). The production of this amino-truncated isoform appears to rescue the classical AHC phenotype, thereby delaying the onset of clinically significant adrenal dysfunction until early adulthood. Thus, this case demonstrates a relatively rare phenomenon by which the clinical severity of an inherited human disease is reduced after alternate translation from a site downstream of a premature stop codon.

Adrenal Hyperplasia, Congenital↗