Congenital hyperinsulinism in two siblings with ABCC8 mutation: same genotype, different phenotypes.

Congenital hyperinsulinism (CHI) is a heterogenous disease caused by insulin secretion regulatory defects, being ABCC8/KCNJ11 the most commonly affected genes. Therapeutic options include diazoxide, somatostatin analogues and surgery, which is curative in focal CHI. We report the case of two siblings (born two years apart) that presented themselves with hypoketotic hyperinsulinemic persistent hypoglycemias during neonatal period. The diagnosis of diffuse CHI due to an ABCC8 compound mutation (c.3576delG and c.742C>T) was concluded. They did not benefit from diazoxide therapy (or pancreatectomy performed in patient number 1) yet responded to somatostatin analogues. Patient number 1 developed various neurological deficits (including epilepsy), however patient number 2 experienced an entirely normal neurodevelopment. We believe this case shows how previous knowledge of the firstborn sibling's disease contributed to a better and timelier medical care in patient number 2, which could potentially explain her better neurological outcome despite their same genotype.

Congenital hyperinsulinism in two siblings with ABCC8 mutation: same genotype, different phenotypes

SUMMARY Congenital hyperinsulinism (CHI) is a heterogenous disease caused by insulin secretion regulatory defects, being ABCC8/KCNJ11 the most commonly affected genes. Therapeutic options include diazoxide, somatostatin analogues and surgery, which is curative in focal CHI. We report the case of two siblings (born two years apart) that presented themselves with hypoketotic hyperinsulinemic persistent hypoglycemias during neonatal period. The diagnosis of diffuse CHI due to an ABCC8 compound mutation (c.3576delG and c.742C>T) was concluded. They did not benefit from diazoxide therapy (or pancreatectomy performed in patient number 1) yet responded to somatostatin analogues. Patient number 1 developed various neurological deficits (including epilepsy), however patient number 2 experienced an entirely normal neurodevelopment. We believe this case shows how previous knowledge of the firstborn sibling's disease contributed to a better and timelier medical care in patient number 2, which could potentially explain her better neurological outcome despite their same genotype.

Severe neurological abnormalities in a young boy with impaired thyroid hormone sensitivity due to a novel mutation in the MCT8 gene.

Monocarboxylate transporter 8 (MCT8) is an active and specific thyroid hormone transporter into neurons. MCT8 mutations cause an X-linked condition known as Allan-Herndon-Dudley syndrome and are characterized by impaired psychomotor development and typical abnormal thyroid function. We describe a 10-year-old boy with severe cognitive disability, axial hypotonia, spastic quadriplegia and sporadic dyskinetic episodes. He initially presented with thyroid dysfunction (high FT3, low rT3, low FT4 and normal TSH) and generalized retardation of the cerebral and cerebellar myelination in brain magnetic resonance imaging. The clinical and laboratory findings led to sequencing of the SLC16A2/MCT8 gene, which identified a novel missense mutation in exon 5. The study of peripheral markers of thyroid function suggests a paradoxical state of thyrotoxicosis in some peripheral tissues. Our patient had a typical clinical presentation at birth but because of the rarity of his disease his diagnosis was not made until the age of 7. The delay can also be explained by the omission of the free T3 assay in the first thyroid evaluation performed. This case therefore highlights the possible benefit of including the T3 assay in the study of patients with severe psychomotor disability of unknown etiology, thus eliminating extra costs for unnecessary complementary diagnostic tests.

Changes in Body Mass Index in Girls with Idiopathic Central Precocious Puberty under Gonadotropin-Releasing Hormone Analogue Therapy: The Spanish Registry.

BACKGROUND: The influence of gonadotropin-releasing hormone analogue (GnRHa) treatment on body mass index (BMI) evolution in girls with idiopathic central precocious puberty (CPP) is unclear. Hence, we aimed to evaluate the effect of GnRHa treatment on BMI-standard deviation score (SDS) from diagnosis of idiopathic CPP until adult height. METHODS: An observational study of girls diagnosed with CPP in Spain was carried out between January 2008 and December 2014. A computer program was designed to process clinical and biological data from patients treated in 55 departments of pediatric endocrinology throughout the country. The inclusion criteria were (1) girls diagnosed with CPP before 8 years of age; (2) born after 1992; (3) with a difference between bone and chronological age of at least 1 year, and (4) with a luteinizing hormone peak >7 U/l during luteinizing hormone-releasing hormone testing. The influence of GnRHa treatment on BMI-SDS evolution was analyzed. RESULTS: Data from 333 girls (22.2% adopted) were evaluated. We report follow-up data at 6, 12, 24, 36, 48 and 60 months and adult height from 269, 232, 198, 153, 105, 56 and 49 girls, respectively. During treatment, there was an increase in BMI-SDS of 0.43 ± 1.17 (95% CI: 0.20-0.64). At adult height (n = 49), BMI-SDS was 1.51 ± 1.38, which was 0.60 ± 1.09 higher than at diagnosis (95% CI: 0.43-0.75). CONCLUSIONS: During treatment with GnRHa, girls experience a significant increase in BMI-SDS that persists after therapy is stopped and adult height has been reached. © 2016 S. Karger AG, Basel.

Precocious presentation of autoimmune polyglandular syndrome type 2 associated with an AIRE mutation.

Autoimmune polyglandular syndrome type 2 (type 2 APS), or Schmidt's syndrome, is defined by the presence of Addison's disease in combination with type 1 diabetes and/or autoimmune thyroid disease. The estimated prevalence of this syndrome is 1.4-4.5 per 100,000 inhabitants and it is more frequent in middle-aged females, whilst it is quite rare in children. Type 2 APS, which shows a pattern of autosomal dominant inheritance with low penetrance, has been associated with HLA specific DR3/DQ2 and DR4/DQ8 haplotypes. However, it has been hypothesized that genetic variability in the AIRE gene, which causing type 1 APS, may play a role in more common organ-specific autoimmune conditions like type 1 diabetes, Hashimoto's disease and type 2 APS, among others. Here we present the case of an 8-year-old girl, with a past medical history of type 1 diabetes diagnosed at the age of 3. She was taken to the Emergency Department because she complained of abdominal pain, nausea and vomiting, and her blood analysis revealed a severe hyponatremia. She also had seizures as a consequence of the hyponatremia and frequent hypoglycemia. She was ultimately found to be suffering from autoimmune primary adrenal insufficiency. The combination of both mentioned conditions, type 1 diabetes and Addison's disease, in the absence of chronic mucocutaneous candidiasis, made a diagnosis of type 2 APS plausible in this girl. The genetic study showed two heterozygous variants: NM_000383.2:C.1411C>T (p. Arg471Cys) in exon 12 and IVS9+6G>A in intron 9 of the AIRE gene. The description of an uncommon case of type 2 APS with precocious presentation associated with an AIRE mutation in a very young girl could help to clarify the role of AIRE in the development of autoimmune diseases.

Congenital hypothyroidism with neurological and respiratory alterations: a case detected using a variable diagnostic threshold for TSH.

We report a case of congenital hypothyroidism (CH) with neurological and respiratory alterations due to a heterozygotic c.374-1G > A mutation of TITF1/NKX2-1. The hypothyroidism was detected using a neonatal screening protocol in which the thyroid stimulating hormone (TSH) threshold is re-set each day on the basis of within-day variability and between-day variation. In this case, the threshold on the day of the initial analysis was 8.2 mIU/L, and the measured TSH level in heel-prick blood was 8.3 mIU/L.

Genetic diagnosis of X-linked dominant Hypophosphatemic Rickets in a cohort study: tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type.

BACKGROUND: Genetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies. METHODS: Forty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test. RESULTS: Mutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH)2D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013). CONCLUSIONS: PHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.

Evolutionary analyses of entire genomes do not support the association of mtDNA mutations with Ras/MAPK pathway syndromes.

BACKGROUND: There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42). METHODS/PRINCIPAL FINDINGS: The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. CONCLUSIONS/SIGNIFICANCE: As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.

Central precocious puberty in children living in Spain: incidence, prevalence, and influence of adoption and immigration.

CONTEXT: No epidemiological data are available on central precocious puberty (CPP) in the general population or in adopted or immigrant children in Spain. OBJECTIVE: We aimed to study the incidence and prevalence of CPP, assess the risk of developing this disorder among adopted and immigrant children, and analyze the predictive variables of CPP associated with intracranial pathology. DESIGN, SETTINGS, AND PATIENTS: An observational study of children diagnosed with CPP in Spain was carried out between January 2008 and January 2010. A computer program was designed to process clinical and biological data and information on 250 patients treated in 34 pediatric endocrinology units throughout the country. RESULTS: Of the patients registered, 226 were girls and 24 were boys. The global incidence rate of CPP was 5.66 cases per million person-years at risk, with an annual incidence ranging between 0.02 and 1.07 new cases per 100,000. The relative risk of CPP in domestic and internationally adopted children compared with those born in Spain was 27.82 (19.99-38.77), whereas the relative risk among immigrants was 1.55 (0.97-2.38). A logistic regression model developed for the study showed that the combined effect of four variables had a significant influence over the presence of organic disease: being male, having been adopted, age at diagnosis, and estimation of adult height. CONCLUSIONS: CPP is a rare disease whose risk markedly increases with both national and international adoption but is not influenced by immigration. These results suggest a psychological influence on CPP.

Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11{beta}-hydroxylase deficiency.

CONTEXT: Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency. OBJECTIVE: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations. METHODS: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein. RESULTS: All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11beta-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively. CONCLUSION: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling in 11OHD.

Hypochondroplasia and Acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation in the fibroblast growth factor receptor 3 gene?

BACKGROUND: Hypochondroplasia (HCH) is a skeletal dysplasia inherited in an autosomal dominant manner due, in most cases, to mutations in the fibroblast growth factor receptor 3 (FGFR3). Acanthosis nigricans (AN) is a velvety and papillomatous pigmented hyperkeratosis of the skin, which has been recognized in some genetic disorders more severe than HCH involving the FGFR3 gene. OBJECTIVE AND DESIGN: After initial study of the proband, who had been consulted for short stature and who also presented AN, the study was extended to the patient's mother and to 12 additional family members. METHODS: Clinical, biochemical and radiological studies were performed on the family. In addition, exons 11 and 13 of FGFR3 were analyzed. RESULTS: The proband and ten relatives presented HCH plus AN and the analysis of FGFR3 showed the p.Lys650Thr mutation. The members with normal phenotypes were non-carriers of the mutation. CONCLUSION: This is the first report of a large pedigree with the clinical phenotype of HCH plus AN due to a FGFR3 mutation, p.Lys650Thr. This finding demonstrates the coexistence of both conditions due to the same mutation and it might represent a true complex, which should be further established by searching for AN in mild HCH patients or for HCH in patients with AN.

Kallmann's syndrome with a novel missense mutation in the KAL1 gene that modifies the major cell adhesion site of the anosmin-1 protein.

Kallmann's syndrome (KS) refers to the association of hypogonadic hypogonadism and anosmia or hyposmia. The X-linked form of the disease is due to mutations in the KAL1 gene that encodes for the protein anosmin-1. We studied the KAL1 gene in a patient with KS and his family by PCR amplification and direct sequencing. A novel missense mutation (V263G) that modifies the major cell adhesion site of the anosmin-1 protein was identified. Our results suggest that this reported mutation is responsible for KS and might help to elucidate the function of an important area of the anosmin-1 protein.

Novel mutation involving the translation initiation codon of the growth hormone receptor gene (GHR) in a patient with Laron syndrome.

Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS) is an autosomal recessive disease due to molecular defects in the GH receptor gene (GHR). Most of the identified mutations are located on the extracelular domain of the receptor. We studied the GHR gene in a patient with LS and found a homozygous missense mutation in exon 2. The novel mutation is an A-->T transversion (ATG -->TTG) that abolishes the translation initiation codon of the GHR gene. This mutation is expected to prevent the translation of the protein. We present clinical, biochemical and molecular evidence of Laron syndrome as the result of a mutation (ATG-->TTG) in the codon for the initial methionine of the GHR gene.