TRANSIENT CONGENITAL HYPOTHYROIDISM IN AN INFANT WITH CONGENITAL NEPHROSIS OF FINNISH TYPE

ABSTRACT. Congenital hypothyroidism was detected on routine neonatal screening in an infant with congenital nephrosis of Finnish type and followed up for 3 years. The hypothyroidism was transient; clinical and biochemical signs and symptoms disappeared after a 20-month period of thyroid replacement therapy and partial improvement of nephrotic symptoms.     

Nephrotic syndrome in children

Nephrotic syndrome is the commonest glomerular disease affecting children and is frequently encountered in general paediatrics. The most common subtype is minimal change nephrotic syndrome which typically occurs in preschool children and responds well to corticosteroids. Another subtype, congenital nephrotic syndrome, also presents in the neonatal period or in early infancy when it may be associated with genetic mutations. Such patients do not respond to immunosuppressant therapy. The study of congenital nephrotic syndromes has identified several causative genetic mutations and there have been significant recent advances in the understanding of disease mechanisms in nephrotic syndrome.Complications of prolonged nephrosis, seen in congenital, frequently relapsing, steroid dependent and particularly steroid resistant nephrotic syndromes can lead to significant morbidity. These include sepsis, thrombosis, hypothyroidism and hyperlipidaemia. It is important to identify and manage these complications. Children with nephrotic syndrome should complete the standard vaccination schedule and in addition should be vaccinated against varicella zoster. Live vaccines should be administered when children are in disease remission and on minimal immunosuppression. The management options for children with frequently relapsing or steroid resistant nephrotic syndrome include additional immunosuppression and several agents have been used in this context. These agents will often require additional therapeutic monitoring.     

Renal Pathology of Prenatally Diagnosed Nephrosis

Congenital Finnish nephrosis is a rare autosomal-recessive disorder, usually fatal at an early age. The disease is prenatally detected through elevation of alpha fetoprotein in the amniotic fluid of pregnancies at risk. This originates from fetal proteinuria. Maternal serum alpha fetoprotein reflects amniotic fluid levels. We describe a case of congenital nephrosis diagnosed through maternal serum screening in a low-risk population. The characteristic histology of congenital nephrosis is demonstrated, and evidence of proteinuria by electron microscopy, light microscopy, and immunofluorescence is presented.     

Renal pathology of prenatally diagnosed nephrosis

Congenital Finnish nephrosis is a rare autosomal-recessive disorder, usually fatal at an early age. The disease is prenatally detected through elevation of alpha fetoprotein in the amniotic fluid of pregnancies at risk. This originates from fetal proteinuria. Maternal serum alpha fetoprotein reflects amniotic fluid levels. We describe a case of congenital nephrosis diagnosed through maternal serum screening in a low-risk population. The characteristic histology of congenital nephrosis is demonstrated, and evidence of proteinuria by electron microscopy, light microscopy, and immunofluorescence is presented.     

The effect of perinatal factors on cord thyroxine concentration

Cord blood thyroxine (T4) concentrations were measured in 4,068 infants from 28 wk gestation to term. Each chart was reviewed for the following factors: delivery by cesarean section, prolonged rupture of membranes, neonatal asphyxia, meconium-stained amniotic fluid, maternal diabetes mellitus and twinning. Each neonate was evaluated for the Idiopathic Respiratory Distress Syndrome, and low (SGA) or high (LGA) birthweight for gestational age. Within each gestational age group, the mean cord T4 value was similar except for a significantly lower mean cord T4 concentration for the term SGA subgroup. Thus, inclusion of the infant with a complicated neonatal course or the infant born to a high-risk mother in mass screening programs for congenital hypothyroidism using cord serum will not increase the number of false-positive T4 values.     

The fairy godmother effect

Two children with congenital nephrotic syndrome are described (one with Finnish-type nephrosis, the other with diffuse mesangial sclerosis). Both children have had a prolonged and sustained clinical response with good physical health and normal growth patterns using captopril and indometacin as their sole treatment. No adverse effects have been noted. We recommend a trial of indometacin and captopril treatment in cases of congenital nephrotic syndrome.     

Congenital and infantile nephrotic syndrome in Thai infants

Congenital and infantile nephrotic syndrome reported from the Eastern world is rare and might be a different entity from that in the West. In a retrospective review of 10 nephrotic syndrome in Thai infants (5 girls and 5 boys), 7 were diagnosed with congenital nephrotic syndrome and 3 with infantile nephrotic syndrome. Two had congenital nephrotic syndrome secondary to congenital syphilis. All had edema, ascites, and failure to thrive. Of the 3 patients tested for thyroid function, all showed hypothyroidism. Two patients developed renal failure. Renal tissue was examined from 4 patients from 3 biopsies and 2 autopsies; only 1 patient showed tubular microcysts. Symptomatic therapy was performed concurrently with penicillin therapy in 2 patients having congenital syphilis. Prednisolone, cyclophosphamide, captopril, and enalapril were tried in some patients, with little effect. Five patients died from respiratory failure complicated by later infection, 1 patient died from renal failure, and 4 patients were lost to follow-up. Nephrotic syndrome in the first year of life in the Eastern world is rare. Prognosis of nephrotic syndrome in Thai infants at this time is still poor.     

Congenital nephrotic syndrome responsive to captopril and indometacin.

Two children with congenital nephrotic syndrome are described (one with Finnish-type nephrosis, the other with diffuse mesangial sclerosis). Both children have had a prolonged and sustained clinical response with good physical health and normal growth patterns using captopril and indometacin as their sole treatment. No adverse effects have been noted. We recommend a trial of indometacin and captopril treatment in cases of congenital nephrotic syndrome.     

南京地区1998-2009年新生儿先天性甲状腺功能减低症筛查及治疗随访结果分析

目的 总结并分析1998年1月- 2009年12月南京地区新生儿先天性甲状腺功能减低症(CH)的筛查结果.方法 采集出生72 h新生儿442 454例的足跟血滴于滤纸上,采用时间分辨免疫法测定滤纸血斑促甲状腺激素(TSH),阳性者召回进一步测定静脉血TSH、三碘甲状腺原氨酸(T3)、四碘甲状腺原氨酸(T4)、游离T3(FT3)、游离T4(FT4)以明确诊断.确诊者立即开始予左旋甲状腺素片(4.3～12.0μg·kg-1·d-1)替代治疗,定期监测其甲状腺功能,测量其身高、体质量,其中68例患儿子智力测试,以评估疗效.结果 12 a共筛查442 454人,确诊CH 183例,发病率为0.41‰,对117例进行随访.初始治疗时间的中位数为18 d(7～67d),初始左旋甲状腺素的平均剂量为7.35 μg·kg-1·d-1.CH患儿的身高、体质量结果基本达到正常参照标准.盖泽尔婴幼儿发展量表(GESELL)测试结果显示1例智能发育落后,8例智能发育迟缓.T4、FT4的治疗前水平与患儿的GESELL测试总分、适应性及精细运动均呈正相关(Pa＜0.05).结论 经筛查确诊的CH患儿,应尽可能早地进行激素替代治疗,可有效改善其预后.因此新生儿筛查及随访治疗工作值得推广和完善.     

Central Congenital Hypothyroidism Detected by Neonatal Screening in Sapporo, Japan (2000–2004): It’s Prevalence and Clinical Characteristics

In Sapporo, Japan, a neonatal screening program for congenital hypothyroidism (CH) has employed measurement of free thyroxine (T4) and TSH in the same filter-paper blood spot. This system has enabled us to identify primary CH and central CH during the neonatal period. The aim of this study was to clarify the prevalence and clinical characteristics of central CH. For this purpose, the screening program requested serum from infants with free T4 concentrations below the cut off value regardless of the TSH levels. Between January 2000 and December 2004, 83,232 newborns were screened and six central CH patients were detected as a result of follow-up of low free T4 and non-elevated TSH screening (1:13,872). This frequency is higher than in other studies. Four patients showed multiple pituitary hormone deficiency with pituitary malformations on magnetic resonance imaging. One patient was diagnosed as having Prader-Willie syndrome. The remaining patient was considered to have isolated central CH. Our study demonstrated that the frequency of central CH is 1:13,872. Free T4 measurement would also be advantageous in early recognition of multiple pituitary hormone deficiency.     

Psychological Development at 7 Years of Age in Children with Congenital Hypothyroidism: Timing and Dosage of Initial Treatment

ABSTRACT. Sixty of 68 consecutive patients detected during the first two years of the Swedish screening programme for congenital hypothyroidism were Griffiths tested at the age 6.5–7.5 years. The test quotients of the patients could not be distinguished from those of reference population. Replacement therapy with 8.7 ± 2.8 μg of l -thyroxine (mean±SD)/kg/d had been started at 15.0 ± 7.1 days of life. Furthermore, normal results on Griffiths tests were also found in 13 patients with delayed normalization of serum TSH, i.e. ≥ 19 mU/l at the age of six weeks, as well as in patients with retarded skeletal maturity and/or very low neonatal serum levels of thyroxine, i.e. < 18 nmol/l and tri-iodothyronine, i.e. <0.92 nmol/l. Our findings indicate that replacement dose of 6–11 μg l -thyroxine/kg/d is adequate and allows normal psychological development if treatment is started early.     

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??Congenital abnormalies of the kidney and urinary tract??CAKUT?? are the main cause of chronic kidney disease ??CKD?? in childhood. Congenital hydronephrosis is a common type of CAKUT and is usually detected by prenatal renal ultrasonography. Severe congenital nephrosis can cause renal injury and end-stage renal disease??ESRD??. The etiology of congenital nephrosis is complicated and involves the abnormal expression of multiple genes. Studies on human tissue specimens and animal models show that oxidative stress?? chronic inflammation and apoptosis result in renal tubular atrophy and renal fibrosis. With advanced biological techniques such as proteomics?? new biological markers are emerging for early disease detection and the choice of the optimal treatment and monitoring.     

Congenital nephrotic syndrome with a novel NPHS1 mutation

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessive disorder. The incidence of CNF is relatively high in Finland but considerably lower in other countries. We encountered a male newborn with CNF, associated with compound heterozygous mutations in nephrosis 1, congenital, Finnish type (NPHS1). The patient was admitted to hospital as a preterm infant. Physical and laboratory findings fulfilled the diagnostic criteria of nephrotic syndrome, and were compatible with a diagnosis of CNF, but there was no family history of the disease. On genetic analysis of NPHS1 a paternally derived heterozygous frame‐shift mutation caused by an 8 bp deletion, resulting in a stop codon in exon 16 (c.2156‐2163 delTGCACTGC causing p.L719DfsX4), and a novel, maternally derived nonsense mutation in exon 15 (c.1978G>T causing p.E660X) were identified. Early genetic diagnosis of CNF is important for proper clinical management and appropriate genetic counseling.     

营养肾病和糖皮质激素对大鼠肝肾组织IGF-I/IGFBPs mRNA表达的影响

目的：探讨营养不良、肾病本身和糖皮质激素作为各自独立因素对大鼠肝肾组织胰岛素样生长因子I/胰岛素样生长因子结合蛋白(IGF-I/IGFBPs) mRNA表达和血清浓度的影响。方法：24只周龄相同体重相近的雄性SD大鼠被随机分成正常对照、食物对照、阿霉素肾病和地塞米松治疗肾病4组。血清IGF-I/IGFBPs和肝肾组织IGF-I/IGFBPs mRNA表达分别采用RIA,Western ligand blot和RT-PCR法检测。结果：①营养不良大鼠血清IGF-I减低,肝肾组织IGF-I mRNA表达增高;肾病本身对血清IGF-I,肝脏IGF-IA mRNA表达无影响,肾脏表达减低;激素治疗使血清IGF-I,肝肾组织IGF-IA mRNA表达均下降。②营养不良大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达减低,肾脏表达正常;肾病本身使大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达增高,肾脏表达减低;激素治疗使肝肾组织IGFBP-2 mRNA表达均下降,但对血清浓度无影响。③营养不良大鼠血清IGFBP-3减低,肝脏IGFBP-3 mRNA表达正常;肾病本身使血清IGFBP-3,肝脏IGFBP-3 mRNA表达均下降;激素治疗使血清IGFBP-3增高,但肝脏IGFBP-3 mRNA表达下降。肾脏IGFBP-3 mRNA表达仅在激素治疗组大鼠能检测到。结论：营养、肾病和糖皮质激素对大鼠肝肾组织IGF-I/IGFBPs mRNA表达的调节具有器官特异性;除血清IGF-I减低部分源于肾脏合成下降外,血清IGFBPs紊乱主要与肝脏合成有关;肾病时IGFBPs可能在不同的水平对IGF-I生物效应发挥调节作用。     

Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type

Congenital nephrotic syndrome (CNS) of the Finnish type due to mutation in the NPHS-1 gene results in massive proteinuria due to structural abnormality in the glomerular slit diaphragm, and is usually refractory to immunosuppressive therapy. Patients eventually require bilateral nephrectomy and renal replacement therapy, with transplantation being the ultimate goal. Post-transplant recurrence of nephrotic syndrome occurs in about 25% of children and is thought to be immune-mediated secondary to antibodies formed against the nephrin protein in renal allograft. Conventional therapy with calcineurin inhibitors (CNI), cyclophosphamide and corticosteroids with or without plasmapheresis often fails to achieve remission resulting in graft loss in 12-16%. There is limited experience with use of rituximab (RTX) in pediatric organ transplant recipients. We report the first case of post-transplant recurrence of nephrotic syndrome in a 4-yr-old child with CNS due to NPHS-1 mutation in whom CNI, corticosteroid and cyclophosphamide therapy was unsuccessful, but who achieved remission after depletion of B cells with RTX, associated with a decrease in the level of anti-nephrin antibodies. The child remains in remission 5 yr following treatment. Our experience suggests that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation in children with CNS.     

Ultrasonography in Congenital Hypothyreosis

To our knowledge, ultrasonography has not so far been used as an additional source of information in the early screening for congenital hypothyreosis. This study demonstrated, firstly, that the normal neonatal thyroid gland could always be recognized by ultrasonography and, secondly, that in congenital hypothyreosis absence of thyroid tissue from the normal site could be detected by ultrasonography, whereas ectopic tissue in the tongue could not readily be identified. The findings may be useful in the diagnosis of congenital hypothyreosis.     

Congenital nephrotic syndrome and persistent hypothyroidism after bilateral nephrectomy

Congenital nephrotic syndrome is commonly associated with hypothyroidism. Thyroid hormone supplementation is recommended as standard of care. The hypothyroidism is postulated to occur secondary to chronic massive proteinuria with loss of thyroid binding globulin, thyroid hormone and iodine. Previous reports have indicated that thyroxin may be discontinued following bilateral nephrectomy. We report our experience with one child with congenital nephrotic syndrome, Finnish type, and hypothyroidism who had a high requirement for thyroxin (100-150 microg/d) from infancy to 4 years of age. Hypothyroidism persisted despite bilateral nephrectomy and later following renal transplantation. However, his thyroxin requirement is now substantially lower (62.5 microg/d) at age 14 years. No goiter was detected clinically and antithyroid antibodies were negative. Thyroid ultrasound and 123I scan revealed a thyroid gland in the anatomically normal location. 123I uptake was elevated, 18% at 6 hours and 51% at 24 hours (normal values: 3-16% at 6 hours and 8-25% at 24 hours). Perchlorate was unavailable for a perchlorate washout study. We speculate that this patient may have an intrinsic problem with thyroid hormone synthesis. It is unclear whether this is related or coincidental to the Finnish nephrotic syndrome. We recommend following thyroid functions closely if thyroxin is discontinued following bilateral nephrectomies in Finnish type congenital nephrotic syndrome.     

Update of newborn screening and therapy for congenital hypothyroidism

Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis. Efforts are ongoing to establish the optimal therapy that leads to maximum potential for normal development for infants with congenital hypothyroidism. Remaining controversy centers on infants whose abnormality in neonatal thyroid function is transient or mild and on optimal care of very low birth weight or preterm infants. Of note, thyroid-stimulating hormone is not elevated in central hypothyroidism. An algorithm is proposed for diagnosis and management. Physicians must not relinquish their clinical judgment and experience in the face of normal newborn thyroid test results. Hypothyroidism can be acquired after the newborn screening. When clinical symptoms and signs suggest hypothyroidism, regardless of newborn screening results, serum free thyroxine and thyroid-stimulating hormone determinations should be performed.     

Dopamine infusion: a possible cause of undiagnosed congenital hypothyroidism in preterm infants.

OBJECTIVE: To describe the possibility that dopamine infusion can prevent early diagnosis of congenital hypothyroidism. DESIGN: Case report. SETTING: Medical neonatal intensive care unit of a tertiary academic medical center. PATIENTS: We report four preterm newborns affected by transient primary congenital hypothyroidism who showed low serum thyroxine and normal thyroid-stimulating hormone concentrations on primary screening performed during treatment with dopamine. INTERVENTIONS: Thyroid reevaluation screening after dopamine discontinuation. MEASUREMENTS AND MAIN RESULTS: Thyroid reevaluation showed elevated thyroid-stimulating hormone levels. CONCLUSION: We emphasize that dopamine capacity to suppress thyroid-stimulating hormone could prevent early diagnosis of congenital hypothyroidism. We suggest all newborns to be tested simultaneously for thyroid-stimulating hormone and thyroxine values at primary screening. A reevaluation of thyroid hormones after dopamine discontinuation is advisable in patients treated with dopamine.     

Congenital nephrotic syndrome with clinical hypothyroidism

A 15 month old boy with typical features of congenital nephrotic syndrome (CNS) is reported, who in addition to the renal pathology had an associated clinical hypothyroidism with low levels of total and free thyroxine and triiodothyronine and an elevated serum TSH. Improvement in the physical parameters and mental status from thyroid hormone replacement therapy is documented.