Paracellin-1 gene mutation with multiple congenital abnormalities

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.

Primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease with an incidence estimated between 1:2,000 and 1:40,000. Ciliated epithelia line the airways, nasal and sinus cavities, Eustachian tube and fallopian tubes. Congenital abnormalities of ciliary structure and function impair mucociliary clearance. As a consequence, patients present with chronic sinopulmonary infections, recurrent glue ear and female subfertility. Similarities in the ultrastructure of respiratory cilia, nodal cilia and sperm result in patients with PCD also presenting with male infertility, abnormalities of left-right asymmetry (most commonly situs inversus totalis) and congenital heart disease. Early diagnosis is essential to ensure specialist management of the respiratory and otological complications of PCD. Diagnostic tests focus on analysis of ciliary function and electron microscopy structure. Analysis is technically difficult and labour intensive. It requires expertise for interpretation, restricting diagnosis to specialist centres. Management is currently based on the consensus of experts, and there is a pressing need for randomised clinical trials to inform treatment.

Two cases of trisomy 16 mosaicism ascertained postnatally

Postnatally ascertained trisomy 16 mosaicism is a rare diagnosis, with only three reported cases to date with no defined clinical phenotype. Trisomy 16 mosaicism diagnosed prenatally is common and associated with variable pregnancy outcomes ranging from stillbirth with multiple congenital abnormalities to an apparently normal newborn, making the genetic counseling very challenging. It is not clear whether uniparental disomy (UPD) 16 contributes to the phenotype, although it has been suggested that maternal UPD 16 affects the rate of intra-uterine growth retardation (IUGR) and congenital anomalies. We report on two further cases of trisomy 16 mosaicism confined to fibroblasts diagnosed postnatally. Patient 1 presented at birth with severe hypospadias, unilateral postaxial polydactyly, and different hair color with midline demarcation. His growth and development were normal at 11 months of age. Patient 2 was born with IUGR, significant craniofacial and body asymmetry, asymmetric skin hyperpigmentation, unilateral hearing loss, scoliosis, VSD, unexplained dilated cardiomyopathy, feeding difficulties, failure to thrive, and recurrent respiratory tract infections. She died at 7 months of age from respiratory failure. These two further cases of postnatally diagnosed trisomy 16 mosaicism highlight the variability of clinical features and outcome in this diagnosis. While Patient 2 presented with typical features of chromosomal mosaicism, Patient 1 had mild and transient features with essentially normal outcome, suggesting that trisomy 16 mosaicism may be under-diagnosed.

Congenital hypothyroidism in a kitten resulting in decreased IGF-I concentration and abnormal liver function tests

A 7-month-old male kitten was presented with chronic constipation and retarded growth. Clinical examination revealed disproportional dwarfism with mild skeletal abnormalities and a palpable thyroid gland. The presumptive diagnosis of congenital hypothyroidism was confirmed by low serum total thyroxine (tT(4)) concentration prior to and after the administration of thyroid stimulation hormone (TSH), increased endogenous TSH concentration and abnormal thyroid scintigraphic scan. The kitten had abnormal liver function tests and decreased insulin-like growth factor 1 (IGF-1) concentration, both of which returned to normal in correspondence with an improvement of the clinical signs after 6 weeks of thyroxine therapy. Congenital hypothyroidism is a rare disease that may present with considerable variation in clinical manifestation. In cases in which clinical signs are ambiguous, disorders such as portosystemic shunt and hyposomatotropism have to be taken into account as differential diagnosis. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 concentrations, test results have to be interpreted carefully.

P450 oxidoreductase deficiency: a new form of congenital adrenal hyperplasia

PURPOSE OF REVIEW: P450 oxidoreductase deficiency--a newly described form of congenital adrenal hyperplasia--typically presents a steroid profile suggesting combined deficiencies of steroid 21-hydroxylase and 17alpha-hydroxylase/17,20-lyase activities. These and other enzymes require electron donation from P450 oxidoreductase. The clinical spectrum of P450 oxidoreductase deficiency ranges from severely affected children with ambiguous genitalia, adrenal insufficiency and the Antley-Bixler skeletal malformation syndrome to mildly affected individuals with polycystic ovary syndrome. We review current knowledge of P450 oxidoreductase deficiency and its broader implications. RECENT FINDINGS: Since the first report in 2004, at least 21 P450 oxidoreductase mutations have been reported in over 40 patients. The often subtle manifestations of P450 oxidoreductase deficiency suggest it may be relatively common. P450 oxidoreductase deficiency, with or without Antley-Bixler syndrome, is autosomal recessive, whereas Antley-Bixler syndrome without disordered steroidogenesis is caused by autosomal dominant fibroblast growth factor receptor 2 mutations. In-vitro assays of P450 oxidoreductase missense mutations based on P450 oxidoreductase-supported P450c17 activities provide excellent genotype/phenotype correlations. The causal connection between P450 oxidoreductase deficiency and disordered bone formation remains unclear. SUMMARY: P450 oxidoreductase mutations cause combined partial deficiency of 17alpha-hydroxylase and 21-hydroxylase. Individuals with an Antley-Bixler syndrome-like phenotype presenting with sexual ambiguity or other abnormalities in steroidogenesis should be analyzed for P450 oxidoreductase deficiency.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Association of congenital, diffuse electrical disease in children with normal heart: sick sinus syndrome, intraventricular conduction block, and monomorphic ventricular tachycardia.

INTRODUCTION Rhythm disturbances in children with structurally normal hearts are usually associated with abnormalities in cardiac ion channels. The phenotypic expression of these abnormalities ("channelopathies") includes: long and short QT syndromes, Brugada syndrome, congenital sick sinus syndrome, catecholaminergic polymorphic ventricular tachycardia, Lènegre-Lev disease, and/or different degrees of cardiac conduction disease. METHODS The study group consisted of three male patients with sick sinus syndrome, intraventricular conduction disease, and monomorphic sustained ventricular tachycardia. Clinical data and results of electrocardiography, Holter monitoring, electrophysiology, and echocardiography are described. RESULTS In all patients, the ECG during sinus rhythm showed right bundle branch block and long QT intervals. First-degree AV block was documented in two subjects, and J point elevation in one. A pacemaker was implanted in all cases due to symptomatic bradycardia (sick sinus syndrome). Atrial tachyarryhthmias were observed in two patients. The common characteristic ventricular arrhythmia was a monomorphic sustained ventricular tachycardia, inducible with ventricular stimulation and sensitive to lidocaine. In one patient, radiofrequency catheter ablation was successfully performed. No structural abnormalities were found in echocardiography in the study group. CONCLUSION Common clinical and ECG features suggest a common pathophysiology in this group of patients with congenital severe electrical disease.

Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort

BACKGROUND & AIMS Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Congenital portosystemic shunt: characterization of a multisystem disease

OBJECTIVES Congenital portosystemic shunts (CPSSs) are rare but increasingly recognized as a cause of important multisystem morbidity. We present new cases and a systematic literature review and propose an algorithm for the identification and care of affected patients. METHODS We reviewed the charts of consecutive patients seen in our pediatric liver clinic between 2003 and 2010 and systematically reviewed the literature of cases with CPSS. RESULTS We identified 316 published cases and 12 patients in our own clinic. Of the published cases (177 male), 185 had an extrahepatic and 131 an intrahepatic portosystemic shunt. Diagnosis was made at any age, from prenatal to late adulthood. Cardiac anomalies were found in 22% of patients. The main complications were hyperammonemia/neurological abnormalities (35%), liver tumors (26%), and pulmonary hypertension or hepatopulmonary syndrome (18%). The spectrum of neurological involvement ranged from changes in brain imaging, subtle abnormalities on neuropsychological testing, through learning disabilities to overt encephalopathy. Spontaneous shunt closure occurred mainly in infants with intrahepatic shunts. Therapeutic interventions included shunt closure by surgery or interventional radiology techniques (35%) and liver transplantation (10%) leading to an improvement of symptoms in the majority. These findings mirror the observations in our own patients. CONCLUSIONS In this largest review of the reported clinical experience, we identify that children with CPSS may present with otherwise unexplained developmental delay, encephalopathy, pulmonary hypertension, hypoxemia, or liver tumors. When CPSS is diagnosed, children should be screened for all of these complications. Spontaneous closure of intrahepatic shunts may occur in infancy. Closure of the shunt is indicated in symptomatic patients and is associated with a favorable outcome.

Enhanced depth imaging optical coherence tomography of congenital cavitary optic disc anomaly (CODA).

AIM To report the finding of extension of the 4th hyper-reflective band and retinal tissue into the optic disc in patients with cavitary optic disc anomalies (CODAs). METHODS In this observational study, 10 patients (18 eyes) with sporadic or autosomal dominant CODA were evaluated with enhanced depth imaging optical coherence tomography (EDI-OCT) and colour fundus images for the presence of 4th hyper-reflective band extension into the optic disc. RESULTS Of 10 CODA patients (18 eyes), five patients (8 eyes) showed a definite 4th hyper-reflective band (presumed retinal pigment epithelium (RPE)) extension into the optic disc. In these five patients (seven eyes), the inner retinal layers also extended with the 4th hyper-reflective band into the optic disc. Best corrected visual acuity ranged from 20/20 to 20/200. In three patients (four eyes), retinal splitting/schisis was present and in two patients (two eyes), the macula was involved. In all cases, the 4th hyper-reflective band extended far beyond the termination of the choroid into the optic disc. The RPE extension was found either temporally or nasally in areas of optic nerve head excavation, most often adjacent to peripapillary pigment. Compared with eyes without RPE extension, eyes with RPE extension were more myopic (mean dioptres -0.9±2.6 vs -8.8±5, p=0.043). CONCLUSIONS The RPE usually stops near the optic nerve border separated by a border tissue. With CODA, extension of this hyper-reflective band and retinal tissue into the disc is possible and best evaluable using EDI-OCT or analogous image modalities. Whether this is a finding specific for CODA, linked to specific gene loci or is also seen in patients with other optic disc abnormalities needs further evaluation.

Vascularised fibula grafts for early tibia reconstruction in infants with congenital pseudarthrosis

Congenital pseudarthrosis of the tibia (CPT) is caused by an ill-defined, segmental disturbance of periosteal bone formation leading to spontaneous bowing, followed by fracture and subsequent pseudarthrosis in the first 2 years of life. The results of conventional treatment modalities (e.g., bracing, internal and external fixation and bone grafting) are associated with high failure rates in terms of persisting pseudarthrosis, malunion and impaired growth. As a more promising alternative, a more aggressive approach, including wide resection of the affected bone, reconstruction with free vascularised fibula grafts from the healthy contralateral leg and stable external fixation at a very early stage has been suggested. Between 1995 and 2007, 10 children (age 12-31 months, median 20 months) suffering from CPT were treated at our institutions according to this principle. Two patients were treated before a fracture had occurred. The length of the fibula graft was 7-9cm. End-to-end anastomoses were performed at the level of the distal tibia stump. The follow-up was 80 months (median, range 12 months to 12 years). Radiologic examination at 6 weeks postoperatively showed normal bone density and structure of the transplanted fibula in all cases and osseous consolidation at 19 of the 20 graft/tibia junctions. One nonunion was sucessfully treated with bone grafting and plate osteosynthesis. Pin-tract infection occurred in three patients. Five children sustained graft fractures that were successfully treated with internal or external fixation. Two patients developed diminished growth of the affected limb or foot; all others had equal limb length and shoe size. At long-term follow-up, tibialisation of the transplant had occurred, and normal gait and physical activities were possible in all children. We conclude that in spite of a relatively high complication rate and the reluctance to perform free flap surgery in infants at this young age, the present concept may successfully prevent the imminent severe sequelae associated with CPT.

Hypokalemic rhabdomyolyisis in congenital tubular disorders: a case series and a systematic review

Hypokalemia is a recognized cause of rhabdomyolysis but very few reports document its association with inborn renal tubular disorders. We report our experience with hypokalemic rhabdomyolysis in 5 pediatric patients affected by inborn renal tubular disorders and the results of a careful review of the literature disclosing 9 further cases for a total of 14 patients (8 male and 6 female subjects, aged between 1.6 and 46, median 16 years). The inborn renal tubular disorders underlying rhabdomyolysis were classic distal renal tubular acidosis (n = 7), Gitelman syndrome (n = 5), classic Bartter syndrome (n = 1), and antenatal Bartter syndrome (n = 1). In 8 patients rhabdomyolysis followed an acute intestinal disease, an upper respiratory illness or the discontinuation of regular medication. Five patients experienced two or more episodes of rhabdomyolysis. In 10 patients the underlying renal tubular disorder was recognized concurrently with the episode of rhabdomyolysis or some weeks later. In conclusion some congenital renal tubular disorders predispose to hypokalemic rhabdomyolysis. Prevention of discontinuation of regular medication and electrolyte repair in the context of acute intercurrent illnesses might avoid the development of hypokalemic rhabdomyolysis.

Lumbar intervertebral disc abnormalities: comparison of quantitative T2 mapping with conventional MR at 3.0 T

To assess the relationship of morphologically defined lumbar disc abnormalities with quantitative T2 mapping.