Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report.

Methylmalonyl-CoA epimerase enzyme (MCEE) is responsible for catalyzing the isomeric conversion between D- and L-methylmalonyl-CoA, an intermediate along the conversion of propionyl-CoA to succinyl-CoA. A dedicated test for MCEE deficiency is not included in the newborn screening (NBS) panels but it can be incidentally identified when investigating methylmalonic acidemia and propionic acidemia. Here, we report for the first time the biochemical description of a case detected by NBS. The NBS results showed increased levels of propionylcarnitine (C3) and 2-methylcitric acid (MCA), while methylmalonic acid (MMA) and homocysteine (Hcy) were within the reference limits. Confirmatory analyses revealed altered levels of metabolites, including MCA and MMA, suggesting a block in the propionate degradation pathway. The analysis of methylmalonic pathway genes by next-generation sequencing (NGS) allowed the identification of the known homozygous nonsense variation c.139C>T (p.R47X) in exon 2 of the MCE gene. Conclusions: Elevated concentrations of C3 with a slight increase in MCA and normal MMA and Hcy during NBS should prompt the consideration of MCEE deficiency in differential diagnosis. Increased MMA levels may be negligible at NBS as they may reach relevant values beyond the first days of life and thus could be identified only in confirmatory analyses.

Fifteen Years of Iodine Prophylaxis in Italy: Results of a Nationwide Surveillance (Period 2015-2019).

CONTEXT: In 2005, a nationwide program of iodine prophylaxis on a voluntary basis was implemented in Italy by law. However, recent data on iodine status are lacking. OBJECTIVE: The aim of this study was to evaluate efficiency, effectiveness, and possible adverse effects (increased occurrence of thyroid autoimmunity and hyperthyroidism) of the Italian iodine prophylaxis program. METHODS: From 2015 to 2019, a nationwide survey was performed. The use of iodized salt was evaluated in a sample of 164 593 adults and in 998 school canteens. A sample of 4233 schoolchildren (aged 11-13 years) was recruited to assess urinary iodine concentration, prevalence of goiter, and thyroid hypoechogenicity on ultrasound, with the latter being an indirect indicator of thyroid autoimmunity. Neonatal TSH values of 197 677 infants screened in regions representative of Northern, Central, and Southern Italy were analyzed to investigate the percentage of TSH values >5.0 mIU/L. Data on methimazole prescriptions were analyzed as indirect indicators of new cases of hyperthyroidism. RESULTS: The prevalence of the use of iodized salt was 71.5% in adult population and 78% in school canteens. A median urinary iodine concentration of 124 µg/L, a prevalence of goiter of 2.2%, and a prevalence of thyroid hypoechogenicity of 5.7% were observed in schoolchildren. The percentage of neonatal TSH values >5.0 mIU/L resulted still higher (5.1%) than the World Health Organization threshold of 3.0%, whereas the prescriptions of methimazole showed a reduction of 13.5%. CONCLUSION: Fifteen years of iodine prophylaxis have led to iodine sufficiency in Italy, although there still is concern about iodine nutritional status during pregnancy.

A young boy with ventricular arrhythmias and thyroid dysgenesis: two genes are not enough?

Abstract Congenital hypothyroidism (CH) may be caused by biallelic variants in the TSHR gene. CH due to thyroid dysgenesis has also been linked to pathogenic variants of the nucleotide kinase 2, homeobox 5 (NKX2-5) gene, which can also cause sudden cardiac death from ventricular arrhythmia. In particular, the NKX2-5 p.Arg25Cys missense variant has been repeatedly reported in patients with congenital heart defects and, more rarely, with hypogonadism. We report the case of a 7 year old boy with ventricular arrhythmias, thyroid dysgenesis and intellectual disability, born from consanguineous Tunisian parents. Exome sequencing and segregation analysis revealed two potentially relevant variants: the NKX2-5 p.Arg25Cys variant (maternally inherited), as well as a single heterozygous TSHR p.Gln90Pro variant (paternally inherited). Of note, a male sibling of the proband, presenting with intellectual disability only, carried the same two variants. No other TSHR variants, or other potentially relevant variants were identified. In this proband, despite the identification of variants in two genes potentially correlated to the phenotype, a definite genetic diagnosis could not be reached. This case report highlights the complexity of exome data interpretation, especially when dealing with families presenting complex phenotypes and variable expression of clinical traits.

A young boy with ventricular arrhythmias and thyroid dysgenesis: two genes are not enough?

Congenital hypothyroidism (CH) may be caused by biallelic variants in the TSHR gene. CH due to thyroid dysgenesis has also been linked to pathogenic variants of the nucleotide kinase 2, homeobox 5 (NKX2-5) gene, which can also cause sudden cardiac death from ventricular arrhythmia. In particular, the NKX2-5 p.Arg25Cys missense variant has been repeatedly reported in patients with congenital heart defects and, more rarely, with hypogonadism. We report the case of a 7 year old boy with ventricular arrhythmias, thyroid dysgenesis and intellectual disability, born from consanguineous Tunisian parents. Exome sequencing and segregation analysis revealed two potentially relevant variants: the NKX2-5 p.Arg25Cys variant (maternally inherited), as well as a single heterozygous TSHR p.Gln90Pro variant (paternally inherited). Of note, a male sibling of the proband, presenting with intellectual disability only, carried the same two variants. No other TSHR variants, or other potentially relevant variants were identified. In this proband, despite the identification of variants in two genes potentially correlated to the phenotype, a definite genetic diagnosis could not be reached. This case report highlights the complexity of exome data interpretation, especially when dealing with families presenting complex phenotypes and variable expression of clinical traits.

Expanded Newborn Screening in Italy Using Tandem Mass Spectrometry: Two Years of National Experience.

Newborn screening (NBS) for inborn errors of metabolism is one of the most advanced tools for secondary prevention in medicine, as it allows early diagnosis and prompt treatment initiation. The expanded newborn screening was introduced in Italy between 2016 and 2017 (Law 167/2016; DM 13 October 2016; DPCM 12-1-2017). A total of 1,586,578 infants born in Italy were screened between January 2017 and December 2020. For this survey, we collected data from 15 Italian screening laboratories, focusing on the metabolic disorders identified by tandem mass spectrometry (MS/MS) based analysis between January 2019 and December 2020. Aminoacidemias were the most common inborn errors in Italy, and an equal percentage was observed in detecting organic acidemias and mitochondrial fatty acids beta-oxidation defects. Second-tier tests are widely used in most laboratories to reduce false positives. For example, second-tier tests for methylmalonic acid and homocysteine considerably improved the screening of CblC without increasing unnecessary recalls. Finally, the newborn screening allowed us to identify conditions that are mainly secondary to a maternal deficiency. We describe the goals reached since the introduction of the screening in Italy by exchanging knowledge and experiences among the laboratories.

Twenty Years of Neonatal Screening for Congenital Adrenal Hyperplasia in North-Eastern Italy: Role of Liquid Chromatography-Tandem Mass Spectrometry as a Second-Tier Test.

BACKGROUND: Newborn screening for congenital adrenal hyperplasia (CAH) based on 17-hydroxyprogesterone (17-OHP) concentration in dried blood spots has been taking place in North-Eastern Italy since 2001. Since 2017, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been introduced, for the first time in Italy, as a second-tier test. AIMS: Our study aims to evaluate, on the one hand, the effectiveness of the newborn screening for CAH after 20 years of testing and, on the other, the impact that the introduction of the second-tier test had on the diagnostic accuracy of the screening program. METHODS: Since 2001 dried blood spots taken from newborns have been screened with a time-resolved fluoroimmunoassay for 17-OHP determination. Over the years, the cut-off levels of 17-OHP were adjusted according to gestational age. Since 2017, a second-tier test in LC-MS/MS was introduced for samples displaying fluoroimmunoassay 17-OHP exceeding the cut-off. RESULTS: In total, 862,521 newborns have been screened over a period of 20 years. The total incidence of 21-hydroxylase deficiency (21-OHD) was 1:25,368, moreover, a case of 11-ß-hydroxylase deficiency was identified. All these diagnoses were genetically confirmed. The sensitivity and specificity of the screening program were 97% and 99.4%, respectively. The use of LC-MS/MS as a second-tier test significantly reduced the recall rate and increased the positive predictive value. CONCLUSIONS: Screening for CAH is useful in the neonatal diagnosis of a classic form of 21-OHD, allowing a precocious treatment of affected children. The introduction of an LC-MS/MS second-tier reduced the recall rate, avoiding unnecessary blood withdrawal and medical evaluations and preventing stress to families. Furthermore, it helped identify rarer forms of CAH.

A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism.

BCKDK is an important key regulator of branched-chain ketoacid dehydrogenase complex activity by phosphorylating and so inactivating branched-chain ketoacid dehydrogenases, the rate-limiting enzyme of the branched-chain amino acid metabolism. We identified, by whole exome-sequencing analysis, the p.His162Gln variant of the BCKDK gene in a neonate, picked up by newborn screening, with a biochemical phenotype of a mild form of maple syrup urine disease (MSUD). The same biochemical and genetic picture was present in the father. Computational analysis of the mutation was performed to better understand its role. Extensive atomistic molecular dynamics simulations showed that the described mutation leads to a conformational change of the BCKDK protein, which reduces the effect of inhibitory binding bound to the protein itself, resulting in its increased activity with subsequent inactivation of BCKDC and increased plasmatic branched-chain amino acid levels. Our study describes the first evidence of the involvement of the BCKDK gene in a mild form of MSUD. Although further data are needed to elucidate the clinical relevance of the phenotype caused by this variant, awareness of this regulatory activation of BCKDK is very important, especially in newborn screening data interpretation.

Newborn Screening for Biotinidase Deficiency. The Experience of a Regional Center in Italy.

Introduction: Biotinidase deficiency (BD) is an autosomal recessive disease causing a defect in the biotin-releasing enzyme. Newborn screening (NBS) allows early diagnosis and treatment, ensuring excellent prognosis. The aim of this study was to describe our experience in the diagnosis, treatment, and follow-up showing key strategies and unsolved questions of the management of BD patients. Methods: We analyzed data of patients identified by the Regional Centre for Newborn Screening of Verona and followed by the Inherited Metabolic Disease Unit of Verona and Neonatal Intensive Care Unit of Bolzano, Italy, from 2014 to 2020. Results: Thirty-seven patients were diagnosed by NBS (five profound and 32 partial BD), with a total incidence of 1:5,996. All were started on biotin at diagnosis and presented no symptoms at follow-up. Analysis of parents and siblings led to identification of five asymptomatic patients with partial BD: one asymptomatic parent and four young siblings. Genetic analysis of the BTD gene identified 17 different genotypes and one mutation not previously known. Discussion: Our data confirm that NBS introduction had a dramatic impact on BD diagnosis, and the incidence has increased significantly compared to other areas. Partial defects are more common than profound and have a distinctive genotype. Partial BD treatment is still controversial even at what dose of biotin and for how long. At the end, BD treatment is very easy and inexpensive and prevents severe neurological damage. Sharing experiences is essential to achieving guidelines for treatment and follow-up and a better genotype-phenotype correlation.

Multiple acyl-COA dehydrogenase deficiency in elderly carriers.

Multiple acyl-CoA dehydrogenase deficiency, or glutaric aciduria type II, is an autosomal recessive disorder of fatty acid oxidation due to defects in electron transfer flavoprotein (ETF) encoded by ETFA and ETFB, or in electron transfer flavoprotein dehydrogenase (ETFDH) encoded by the ETFDH gene. The disease may present as a severe neonatal onset form and a mild late-onset form which is heterogeneous for the age at onset and clinical presentation. We describe two patients in their seventies, referred for a nonspecific myopathy, which resulted to manifest carriers of ETFDH gene mutation. Treatment with riboflavin and L-carnitine improved the clinical picture and the biochemical profile. This condition should be included in the differential diagnosis of myopathies even at an old age.

Children with premature pubarche: is an alterated neonatal 17-Ohp screening test a predictive factor?

BACKGROUND: Neonatal screening for 21 hydroxylase deficiency is designed to detect classical form of congenital adrenal hyperplasia (CAH). It is still unclear whether newborns who result false positives at neonatal screening might later develop signs of androgen excess. The aim of this study is to verify whether a slightly elevated 17-OHP at newborn screening is a predictive factor for premature pubarche. METHODS: We evaluated all infants born between 2001 and 2014 with premature pubarche. In case of increased bone age, they were submitted to functional tests to find out the cause of their symptoms. Their 17-OHP values at newborn screening for CAH were reconsidered. RESULTS: We identified 330 patients (269 females, 61 males) with premature pubarche. All these children had a normal 17-OHP at newborn screening with the exception of a child, born preterm and not affected by CAH. CONCLUSIONS: An elevated 17-OHP at newborn screening is not a predictive factor for premature pubarche. A likely cause of increased 17-OHP level at screening is an immaturity of adrenal gland or a neonatal stress. Therefore a strict follow up of these neonates during childhood is not necessary.

High-protein goat's milk diet identified through newborn screening: clinical warning of a potentially dangerous dietetic practice.

OBJECTIVE: Breast-feeding is an unequalled way of providing optimal food for infants' healthy growth and development and the WHO recommends that infants should be exclusively breast-fed for the first 6 months of life. For mothers who are unable to breast-feed or who decide not to, infant formulas are the safest alternative. Despite recommendations, it is possible that parents make potentially harmful nutritional choices for their children because of cultural beliefs or misinformation on infant nutrition. We describe a possible health risk of not breast-feeding, highlighting a potentially dangerous dietetic practice. Design/Setting/Subjects We report the case of a newborn who was fed with undiluted goat's milk because her mother could not breast-feed and was not aware of infant formulas. RESULTS: The dietary mistake was detected because of a positive expanded newborn screening result, characterized by severe hypertyrosinaemia with high methionine and phenylalanine levels, a pattern suggestive of severe liver impairment. The pattern of plasma amino acids was related to a goat's milk diet, because of its very different composition compared with human milk and infant formula. CONCLUSIONS: Our experience demonstrates that, when breast-feeding is not possible or is not exclusive, infants may be at risk of dangerous nutritional practices, including diets with very high protein content, such as a goat's milk diet. Families of not breast-fed infants may need appropriate advice on safe alternatives for infant nutrition to avoid the risks of inappropriate diets.

Congenital hypothyroidism with delayed TSH elevation in low-birth-weight infants: incidence, diagnosis and management.

OBJECTIVE: To evaluate the incidence of congenital hypothyroidism (CH) with delayed TSH elevation among low-birth-weight (LBW) newborns in North-Eastern Italy and to verify if they need a second or third screening. DESIGN: Analysis of clinical and biochemical data of newborns affected by CH with delayed TSH elevation identified by neonatal screening. METHODS: Data of all newborns with birth weight (BW) <2500 g and evidence of delayed TSH elevation at newborn screening were collected between 2011 and 2014. Confirmatory tests were based on serum TSH and FT4 levels. All their clinical signs at diagnosis were reported. RESULTS: 57.5% of LBW newborns with delayed TSH increase at neonatal screening presented a CH with delayed TSH elevation and began a treatment with l-thyroxine. The incidence of this condition in North-Eastern Italy is therefore 1:908. The remaining infants presented a subclinical hypothyroidism (21.25%) or a complete normal serum thyroid function (21.25%). These data could be drawn only from a retesting strategy of neonatal screening. CONCLUSIONS: Our report describes the incidence of CH with delayed TSH rise in North-Eastern Italy and differentiates this clinical condition from other thyroid dysfunctions of preterm or LBW newborns. The second-screening strategy for CH in neonates with BW < 2500 g proved useful in detecting newborns who otherwise would not be identified at the first screening.

Analysis of the d3-growth hormone receptor polymorphism in large cohorts of small, appropriate and large for gestational age newborns.

BACKGROUND: Several studies evidenced a possible role of the d3-Growth Hormone Receptor (GHR) polymorphism in fetal growth. The GHR genotype distribution was studied in small (SGA) and appropriate (AGA) for gestational age newborns but never in the large (LGA) for gestational age babies. The aim of this study was to evaluate the frequencies of this polymorphism in a large cohort of SGA, AGA and LGA newborns. METHODS: A total of 536 healthy newborns, randomly selected among the infants referred to the Italian North-Eastern centre for endocrinological and metabolic newborn screening, were enrolled: 192 SGA, 200 LGA and 144 AGA. Weight was recorded at birth. Isoforms of d3-GHR gene (fl/fl, d3/fl, and d3/d3) were analysed. RESULTS: The analysis of the GHR genotype evidenced a lower frequency of the d3/d3 genotype in SGA cohort compared to the AGA population (P=0.005), or to the total population (P=0.035). No differences were found in the genotypic distribution between LGA and AGA population (P=0.373), or between LGA and the whole population (P=0.292). CONCLUSIONS: d3/d3 GHR genotype was found twice as frequent in AGA and LGA cohorts compared to SGA subjects, whereas no significant differences in the frequency distribution of the GHR genotypes between LGA and AGA newborns were detected. The data leads to the exclusion of the GHR exon 3 deletion polymorphism as a possible genetic factor leading to LGA pregnancies.

Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism.

BACKGROUND: Congenital hypothyroidism is often secondary to thyroid dysgenesis, including thyroid agenesis, hypoplasia, ectopic thyroid tissue or cysts. Loss of function mutations in TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1 genes are responsible for some forms of inherited congenital hypothyroidism, with or without hypoplastic thyroid. The aim of this study was to analyse the PAX8 gene sequence in several members of the same family in order to understand whether the variable phenotypic expression, ranging from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism, could be associated to the genetic variant in the PAX8 gene, detected in the proband. METHODS: We screened a hypothyroid child with thyroid hypoplasia for mutations in PAX8, TSHR, NKX2.1, NKX2.5 and FOXE1 genes. We studied the inheritance of the new variant R133W detected in the PAX8 gene in the proband's family, and we looked for the same substitution in 115 Caucasian European subjects and in 26 hypothyroid children. Functional studies were performed to assess the in vitro effect of the newly identified PAX8 gene variant. RESULTS: A new heterozygous nucleotide substitution was detected in the PAX8 DNA-binding motif (c.397C/T, R133W) in the proband, affected by congenital hypothyroidism with thyroid hypoplasia, in his older sister, displaying a subclinical hypothyroidism associated with thyroid hypoplasia and thyroid nodules, in his father, affected by hypothyroidism with thyroid hypoplasia and thyroid nodules, and his first cousin as well, who revealed only a subclinical hypothyroidism. Functional studies of R133W-PAX8 in the HEK293 cells showed activation of the TG promoter comparable to the wild-type PAX8. CONCLUSIONS: In vitro data do not prove that R133W-PAX8 is directly involved in the development of the thyroid phenotypes reported for family members carrying the substitution. However, it is reasonable to conceive that, in the cases of transcriptions factors, such as Pax8, which establish several interactions in different protein complexes, genetic variants could have an impact in vivo.

3-hydroxyacyl-coenzyme a dehydrogenase deficiency: identification of a new mutation causing hyperinsulinemic hypoketotic hypoglycemia, altered organic acids and acylcarnitines concentrations.

The human HADH gene encodes the short-chain-L-3-hydroxyacyl-CoA dehydrogenase, the enzyme which catalyzes the third step of the ß-oxidation of the fatty acids in the mitochondrial matrix. Loss-of-function mutations in the HADH gene lead to short-chain-L-3-hydroxyacyl-CoA dehydrogenase deficiency, an autosomal recessive genetic defect of unknown prevalence with a wide spectrum of phenotypic variability. As in other metabolic diseases, the diagnostic relevance of the biochemical evaluations, plasma acylcarnitines, and urinary organic acids, are crucially dependent on the clinical conditions of the patient during specimen collection.This paper describes the eighth patient carrying a HADH gene mutation, a new homozygous deletion c.565delG leading to an early stop codon (p.V116Wfs124X), in an infant with hyperinsulininemic hypoglycemia, displaying abnormal patterns of plasma acylcarnitines and urinary organic acids. We conclude that, when the residual catalytic activity of the mutated enzyme is seriously reduced, the biochemical hallmarks of the disease, namely plasma 3-hydroxybutyrylcarnitine and urinary 3-hydroxyglutaric acid, are invariably present.

Possible andrologic markers in elevated neonatal 17-hydroxyprogesterone.

In this prospective study, we analyzed 30 male infants with increased neonatal 17-hydroxyprogesterone (17OH-P) (patients) and for comparison 52 age-matched healthy babies (control subjects) with the aim of investigating the hypothalamic-pituitary-testis axis in the first 6 months of life. Although T, FSH, and LH levels were not significantly different in patients and control subjects, inhibin B was higher in patients than in control subjects. Therefore we suggest a clinical follow-up of these babies during childhood and puberty to verify the evolution of their condition.

Subclinical hypothyroidism in children and adolescents: a wide range of clinical, biochemical, and genetic factors involved.

OBJECTIVE: The aim of the study was to examine clinical characteristics, biochemical parameters, and TSH-R gene variations in children and adolescents with subclinical hypothyroidism (SH) in order to evaluate their pattern of distribution in SH. PATIENTS: We enrolled 88 patients, each having at least two TSH measurements above the upper limit of the reference range with normal free thyroid hormones and negative thyroid autoantibodies. MAIN OUTCOME MEASURES: Clinical characteristics included height, weight, family history of thyroid diseases, thyroid volume, and echogenicity at ultrasonography. Biochemical parameters included TSH, free thyroid hormones, thyroid autoantibodies, and adjusted daily urinary iodine excretion (UIE). Genetic variations in the TSH-R gene were assessed. RESULTS: The prevalence of overweight/obesity, positive family history of thyroid diseases, and thyroid hypoechogenicity was 28.4, 45.5, and 22.7%, respectively. Median TSH was higher in overweight/obese patients than in normal-weight ones (7.4 vs. 5.7 muIU/ml; P = 0.04) and in overweight/obese patients with hypoechogenicity than in those with normal ultrasound pattern (8.5 vs. 6.8 muIU/ml; P = 0.04). Adjusted daily UIE was lower in subjects without than in those with a positive family history of thyroid diseases (81 vs. 120 mug/d; P = 0.001). The prevalence of a positive family history of thyroid diseases was 1.9-fold higher in patients with nonsynonymous mutations in the TSH-R gene than in patients without any mutation (80 vs. 42%; P = 0.03). A novel mutation at position 1559 in exon 10 (W520X) was detected in one child. CONCLUSIONS: Overweight/obesity, thyroid hypoechogenicity, and nonsynonymous mutations in the TSH-R gene are characterizing features of a large portion of SH children.

Anthropometric traits and aging: a cross-sectional survey in diabetic elderly women.

The aim of this cross-sectional study was to identify the peculiar anthropometric changes in elderly diabetic women aged 70 years and above. The subjects were 91 women suffering from type-2 diabetes and 101 healthy female controls; all these 192 North-Italian women were aged 70 years or over. Eight anthropometric measurements were collected for each subject. We observed significant anthropometric differences between diabetic women and controls. The changes with aging were more evident in women suffering from type-2 diabetes than in controls of the same age groups. In conclusion, the diabetic women are more in overweight than the controls. Moreover, diabetes resulted associated with an accelerated process of aging in anthropometric traits.

Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated hyperthyrotrophinaemia.

OBJECTIVES: To establish the role of new TSH receptor (TSHr) variants (P27T, E34 K, R46P, D403N, W488R and M527T) recently identified in children with congenital hypothyroidism (CH) or subclinical hypothyroidism (SH) with a thyroid gland of normal size. DESIGN AND MEASUREMENTS: TSHr variants were obtained by mutagenesis. Wild-type (wt) and TSHr mutants were expressed in COS cells and cAMP assay, (125)I-TSH binding and microchip flow cytometry analyses were performed. RESULTS: D403N and M527T mutants showed a lower cAMP response to bovine TSH (bTSH) with respect to the wtTSHr. R46P and W488R mutants did not show any response to bTSH stimulation in terms of cAMP production. The E34 K mutant showed a significantly lower cAMP response to stimulation with bTSH, while P27T had a lower cAMP response only to the highest dose of bTSH used. P27T, E34 K, D403N and M527T mutants showed a lower TSH binding capacity with respect to the wtTSHr. R46P and W488R mutants did not show any TSH binding. CONCLUSIONS: E34 K, D403N, M527T, R46P and W488R TSHr variants seem to cause a functional abnormality of the receptor which is responsible for the observed phenotype. The P27T TSHr variant does not seem to play a functional role in the pathogenesis of CH and should be considered as a polymorphism.

Prepubertal serum inhibin B in cryptorchid infants and in monorchid boys with compensatory testicular hypertrophy.

OBJECTIVE: To investigate the prepubertal serum inhibin B levels in monorchid boys with compensatory testicular hypertrophy (CTH) and in surgically treated cryptorchid boys with normal testicular volume. DESIGN: Prospective study. SETTING: Pediatric Division, University of Verona, Italy. PATIENT(S): Thirty-two prepubertal boys: 11 monorchids with CTH and 21 cryptorchids. For comparison we analyzed 15 healthy boys. MAIN OUTCOME MEASURE(S): All patients underwent a GnRH agonist test. Inhibin B measurement was performed at basal time. RESULT(S): There was a significant difference in mean testicular volume between monorchid and cryptorchid or healthy children, with boys with CTH evidencing larger testicle volume. There was no significant difference in inhibin B levels between boys with CTH and cryptorchid, but the levels were significantly lower in both groups than in the control group. Boys with CTH had significantly higher serum levels of basal FSH than children with cryptorchid. The FSH peak response to GnRH agonist stimulation was significantly higher in boys with CTH than in those with cryptorchid. CONCLUSION(S): Monorchid infants with CTH showed low inhibin B and high FSH levels. Our finding may confirm the hypothesis that CTH is unable to prevent testicular insufficiency in adulthood. We suggest an early hormonal evaluation of boys with CTH at puberty, together with early sperm analysis.