Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.

We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1-encoding sphingosine-1-phosphate (S1P) lyase 1. SGPL1 catalyzes the irreversible degradation of endogenous and dietary S1P, the final step of sphingolipid catabolism, and of other phosphorylated long-chain bases. S1P is an intracellular and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry. Vascular alterations were present in a patient's renal biopsy, in line with changes seen in Sgpl1 knockout mice that are compatible with a developmental defect in vascular maturation. In conclusion, loss of SGPL1 function is associated with CNS, adrenal calcifications, and hypogonadism.

Neonatal outcome of macrosomic infants: an analysis of a two-year period.

OBJECTIVE: To assess the neonatal outcome of macrosomic neonates in uncomplicated, singleton, term deliveries. STUDY DESIGN: A retrospective analysis was performed on 5738 live-born term neonates born in the period 2008-2009. The neonatal outcomes were compared between two birth weight (BW) groups: the macrosomic neonates born with BW≥4000g and a control group: 2500-3999g. There were 410 (7.1%) neonates in the macrosomic group, 4757 (82.9%) in the control group, while 571 (10.0%) were less than 2500g at birth. A correlation analysis of two subgroups of the macrosomic neonates (4000-4499g vs. ≥4500g) was also carried out. RESULTS: The rate of caesarean section (CS) was significantly higher in the macrosomic group as compared with the control group (49.3% vs. 39.9%), as were the prevalences of hypoglycaemia (6.1% vs. 2.9%), adrenal haemorrhage (0.98% vs. 0.15%) and the male to female ratio (2.15 vs. 0.95). The rate of icterus was significantly higher in the control group (30.4% vs. 18.5%). The macrosomic subgroups were similar in many aspects, but we found significantly more neonates in the higher weight subgroup as regards a low Apgar score, clavicle fracture and the need for intensive care. CONCLUSIONS: The macrosomic infants were born in good general condition, although those with BW ≥4500g more frequently had an adverse outcome. The macrosomic and control groups' data revealed significant differences in the rate of CS, the male to female ratio, hypoglycaemia and adrenal haemorrhage.

Adrenal masses associated with Beckwith Wiedemann syndrome in the newborn.

Adrenal cystic lesions are rare and may be associated with both complete and incomplete Beckwith syndrome (BWS). Because the adrenal gland often houses malignant lesions, differentiation between benign and malignant lesions of the gland, although usually difficult, is very necessary from the point of view of management. Here we present our experience in a case of incomplete BWS with adrenal cystic lesion and review of the literature.

Clinical features and surgical outcome of a suprarenal mass detected before birth.

PURPOSE: With the widespread use of the obstetrical ultrasound, identification of a fetal suprarenal mass has become more common. Most of these masses prove to be congenital neuroblastomas (CNB), but the diagnosis is often confused with other benign lesions and the postnatal management remains to be controversial. METHODS: The medical records of 18 patients that underwent primary surgical excision for an antenatally detected suprarenal mass, between January 1995 and April 2009, were reviewed. The clinical, radiological, surgical, and pathological data were collected. Staging evaluation was performed after histological confirmation of the CNB. RESULTS: There were 13 cases of CNB, 1 adrenal cyst, 2 adrenal hemorrhages, and 2 pulmonary sequestrations. The differential diagnosis was impossible before surgery. Most of the CNBs were stage I (N = 11), with 1 stage IV and 1 stage IV-S. Four patients (3 stage I and 1 stage IV-S) had more than one copy of N-myc gene. The stage I patients were cured by surgery alone, and stage IV patients underwent nine cycles of adjuvant chemotherapy and currently have no evidence of disease. The five benign lesions were cured with excision alone. There were no postoperative complications. CONCLUSION: For early diagnosis and treatment, surgical excision should be considered as the primary therapy for an antenatally detected suprarenal mass. The surgery can be safely performed during the neonatal period and provides a cure in most cases.

A case of X-linked adrenal hypoplasia congenita, central precocious puberty and absence of the DAX-1 gene: implications for pubertal regulation.

BACKGROUND/AIMS: X-linked adrenal hypoplasia congenita (AHC) is typically associated with DAX-1 mutations and hypogonadotropic hypogonadism. However, atypical cases of X-linked AHC in association with central precocious puberty and even normal puberty have rarely been reported, although the mechanism of action remains unknown. CASE REPORT: This is a case report of a boy with X-linked AHC associated with Duchenne muscular dystrophy, whose clinical presentation led to analysis of the DAX-1, glycerol kinase (GK1) and dystrophin genes, which were amplified by polymerase chain reaction, with Southern blot analysis of the AHC locus. RESULTS: There was a non-contiguous deletion of the DAX-1 and GK1 genes, with deletion of the dystrophingene from exons 3 to 79. CONCLUSION: This is the first report of X-linked AHC, central precocious puberty in the absence of the DAX-1 gene. The fact that a 'loss of function' DAX-1 mutation can be associated with hypogonadotropic hypogonadism, precocious and normal puberty, suggests that DAX-1 is but one of several transcription factors which regulate puberty, and provides further evidence that other transcription factors may interact with DAX-1 and influence gonadal regulation in a complex, but hierarchical fashion.

[Rare congenital defects of adrenal steroidogenesis]. / Rzadkie zaburzenia wrodzone steoidogenezy nadnerczowej.

Congenital defects of adrenal steroidogenesis comprises a group of autosomally recessive disorders, which are usually caused by inactivating mutations in single enzymes involved in adrenal steroid biosynthesis. Each of the defects causes different biochemical consequences and clinical features. A different degree of enzyme dysfunction is responsible for a wide range of phenotypic expression even in the same disorder. The basis for the diagnosis of inborn errors of steroidogenesis are often refined methods for steroid determination. Because these defects may result in life-threatening conditions and, if not treated, lead to serious complications, its is essential to consider their presence in a differential diagnosis of various symptoms. Deficiency of 21-hydroxylase, the most common of these disorders, has been recently extensively reviewed. Therefore, this paper discusses the etiopathogenesis, clinical manifestation, biochemical abnormalities and management of other less frequent defects of adrenal steroidogenesis.

Disorders of adrenal development.

Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia. Adrenal hypoplasia can occur: (1) secondary to defects in pituitary adrenocorticotropin (ACTH) synthesis, processing and release (secondary adrenal hypoplasia; e.g. HESX1, LHX4, SOX3, TPIT, pituitary POMC, PC1); (2) as part of several ACTH resistance syndromes (e.g. MC2R/ACTHR, MRAP, Alacrima, Achalasia, Addison disease), or as (3) a primary defect in the development of the adrenal gland itself (primary adrenal hypoplasia; e.g. DAX1/NR0B1 - dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome 1). Indeed, the X-linked form of primary adrenal hypoplasia due to deletions or mutations in the orphan nuclear receptor DAX1 occurs in around half of male infants presenting with a salt-losing adrenal crisis, where no obvious steroidogenic defect (e.g. 21-hydroxylase deficiency), metabolic abnormality (e.g. neonatal adrenoleukodystrophy) or physical cause (e.g. adrenal haemorrhage) is found. Establishing the underlying basis of adrenal failure can have important implications for investigating associated features, the likely long-term approach to treatment, and for counselling families about the risk of other children being affected.

Bilateral renal venous thrombosis and adrenal hemorrhage: sequential prenatal US with postnatal recovery.

A neonate presented with bilateral renal venous thrombosis (RVT) and adrenal hemorrhage. Serial fetal ultrasonography showed progressive development of severe atrophy of one kidney and mild atrophy of the other. At sequential postnatal imaging, both kidneys showed progressive growth. Bilateral fetal RVT is quite uncommon, and postnatal recovery of a kidney severely affected by RVT is very rare.

The rare occurrence of absent adrenals in a term infant: a case report and review of the literature.

A female infant (gestational age, 37 weeks) presented with respiratory distress and pulmonary hypertension. Incidental to her clinical course, she was discovered by abdominal ultrasound to have absent adrenal glands bilaterally. This is the first case report of congenitally absent adrenal glands noted at birth. The exons of the patient's SF-1 gene were sequenced, and despite identifying a single nucleotide polymorphism that preserves proline at position 125 of SF-1, none of the previously identified mutations were detected in our samples. The known role of SF-1 and its mutations in adrenal gland development are discussed.

Management of severe hyperbilirubinemia in the newborn: adrenal hematoma revisited.

A 4-day-old male infant presented with complaints of jaundice on the third day of life. He was full-term and appropriate for gestational age and born to unrelated parents. All laboratory investigation tests were normal except total serum bilirubin of 27.4 mg/dl with a direct bilirubin 0.29 mg/dl. Abdominal and cranial ultrasonography (US) was performed on sixth day of life because of severe hyperbilirubinemia. Abdominal US revealed adrenal hematoma. Enclosed hematomas may cause significant unconjugated hyperbilirubinemia in absence of other high-risk conditions.

Inappropriate tall stature and renal ectopy in a male patient with X-linked congenital adrenal hypoplasia due to a novel missense mutation in the DAX-1 gene.

Mutations in DAX-1 gene cause congenital adrenal hypoplasia (AHC). We present a male patient affected by X-linked adrenal hypoplasia congenita due to a novel DAX-1 missense mutation. The mutation V287G affects the C-terminal end of the DAX-1 protein which plays an important role in functioning of the receptor. In addition, our patient presented an inappropriate tall stature and renal ectopy, which have not been described in AHC so far.

Identification of novel mutations of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita.

OBJECTIVE: X-linked adrenal hypoplasia congenita (AHC) is a condition clinically featuring adrenal insufficiency and hypogonadotropic hypogonadism caused by mutations of DAX-1. This study was undertaken to characterize the molecular defects of DAX-1 in 3 unrelated Korean patients with AHC. PATIENTS AND METHODS: Patient 1 is a 6-year-old boy who presented with a salt-losing adrenal crisis in the neonatal period. Patient 2 is a 3-year-old boy who manifested aspiration pneumonia and adrenal insufficiency at the age of 1 month. Patient 3 is a 7-year-old boy who developed an adrenal crisis at the age of 3 days. In each of these patients, DAX-1 was analyzed by direct DNA sequencing after polymerase chain reaction amplification of the entire coding region. RESULTS: Direct sequencing of DAX-1 revealed two novel mutations, 1156_1157delCT in patient 1 and another novel nonsense mutation W105X in patient 2. Patient 3 had complete deletion of DAX-1. In patient 3, serum transaminases and creatine kinase levels were elevated while the glycerol kinase activity of leukocytes was decreased. Markedly elevated glycerol excretion was detected by urine organic acid analysis. Patient 3 was diagnosed as Xp21 contiguous gene syndrome associated with deletions of the entire IL1RAPL, GK genes and the C-terminal region of DMD gene. CONCLUSIONS: Two novel mutations of DAX-1 were detected in 2 unrelated patients with AHC, and complete deletion of DAX-1 in a patient with Xp21 contiguous gene syndrome who also presented with glycerol kinase deficiency, Duchenne muscular dystrophy, and AHC.

Non-iatrogenic pathology of the preterm infant.

Non-iatrogenic anatomical findings at autopsy provide insight into preterm infant physiology. The different patterns of lipid accumulation in the adrenal may correspond to long-term differences in stress response. Cardiac papillary muscle infarction occurs with asphyxia or shock and can explain myocardial dysfunction. Underdevelopment of preterm kidneys may correlate with susceptibility to renal disease and hypertension in adult life. Immaturity of the lung or immature responses to inflammation, rather than high oxygen concentrations or high ventilation pressures, may underlie chronic lung disease in premature infants. Hepatic extramedullary haematopoiesis is normal but, if excessive or abnormally persistent, can be an indicator of fetal disease. Hypertrophic somatostatin islet cells found with intra-uterine growth retardation may correlate with low serum insulin. Thymic involution may mark the degree of stress. Small thyroglobulin stores may limit the premature neonate's initiation of thermogenesis.