Gitelman syndrome and primary hyperparathyroidism: a rare association.

Gitelman syndrome(GS) is a rare autosomal recessive salt-losing tubulopathy of young adults, characterised by hypokalaemia, hypomagnesaemia, hypocalciuria and secondary hyperaldosteronism. Hypercalcaemia due to hypocalciuria in these patients is extremely rare.A 25-year-old healthy woman was referred to the Endocrinology clinic for evaluation of persistent hypokalaemia. She presented with fatigue, myalgias, cramps and paraesthesia. Her physical examination was normal. Laboratory workup revealed: K+ 2.7 mEq/L (r.v.3.5-5.1), 24 hours urinary K+ 84.7 mEq/24 hours (r.v.25-125), Mg2+ 0.71 mg/dL (r.v.1.6-2.6), 24 hours urinary Mg2+ 143.1 mg/24 hours (r.v.73-122), Ca2+ 12 mg/dL (r.v.8.4-10.2), aldosterone 47.1 ng/mL (r.v. 4-31) and active renin 374.7 uUI/mL (r.v.4.4-46.1). She was diagnosed with GS and was treated with spironolactone, oral K+ and Mg2+ supplementation. Further investigation confirmed hypercalcaemia due to primary hyperparathyroidism owing to a single parathyroid adenoma. Following parathyroidectomy serum calcium normalised.Current knowledge favours that hypomagnesaemia in patients with GS protects them from hypercalcaemia. In this context of multiple electrolyte imbalances, correction of hypomagnesaemia is a challenge and should be done carefully. Like in our patient, aetiology of hypercalcaemia should be promptly diagnosed and reversed.

Concomitant presence of JAK2V617F mutation and BCR­ABL translocation in two patients: A new entity or a variant of myeloproliferative neoplasms (Case report).

Myeloproliferative neoplasms (MPNs) are classically divided into BCR RhoGEF and GTPase activating protein (BCR)-ABL proto­oncogene 1 non­receptor tyrosine kinase (ABL) positive chronic myeloid leukemia (CML) and BCR­ABL negative MPNs, including essential thrombocythemia (ET). One of the major diagnostic criteria for ET is the absence of the philadelphia chromosome, thus when present it is almost indicative of CML. ET and CML are considered to be mutually exclusive; however, there are rare situations in which patients with ET present positive BCR­ABL without the features of CML. Although from the literature review, the frequency of JAK2V617F mutation and BCR­ABL translocation coexistence in MPNs is low, it may be higher than expected. The current study reported cases of two patients with an initial diagnosis of ET in the presence of JAK2V617F mutation and BCR­ABL translocation by fluorescent in situ hybridization. Both patients presented with a heterozygous BCR­ABL translocation, and absence of p190 and p210 transcripts, seemingly a der(9) in the background of an ET JAK2V617F mutation.

Atypical haematological presentation in a case of polycythaemia vera with a new variant mutation detected in exon 12: c.1605G>T (p.Met535Ile).

One of the major genetic insights into the pathogenesis of polycythaemia vera included the identification of the somatic point gain-of-function mutations in Janus kinase 2 gene-first JAK2V617F on exon 14, present in 95%-97% of the cases, and later on exon 12. In the literature, we can find some reported studies where different exon 12 mutations are identified. Unlike patients with JAK2V617F mutation in exon 14, the mutation at exon 12 is not usually associated with an increase in the three haematopoietic series (erythrocytosis, leucocytosis and thrombocytosis). It appears to be associated with a distinct syndrome, mostly characterised by isolated and more marked erythrocytosis, independently of the mutational variant. We report here the case of a patient who is JAK2exon 12 positive, presenting a novel mutation-c.1605G>T (p.Met535Ile)-associated with c.1612C>T (p.His538Tyr) mutation previously described, evidencing an atypical clinical phenotype.

Piebaldism and neurofibromatosis: state of knowledge.

Despite progress in understanding the molecular basis, the diagnosis of neurofibromatosis 1 (NF 1) is based on clinical criteria, established by the National Institute of Health (NIH) Consensus Conference in 1987. The association of NF1 and piebaldism has been reported, but some authors disagree with this co-occurrence. In the light of present knowledge, we highlight that both entities might co-exist in the same patient.

Kallmann syndrome in a female adolescent: a new mutation in the FGFR1 gene.

The Kallmann syndrome is characterised by the association of hypogonadotropic hypogonadism and hypo/anosmia. It represents a phenotypically and genotypically heterogeneous clinical entity, with six genes identified so far in the literature-KAL1, FGFR1, PROKR2, PROK2, CHD7 and FGF8. Mutations in the FGFR1 gene can be found in approximately 10% of the patients. The authors present the case of a female adolescent with hypogonadotropic hypogonadism and impaired olfactory acuity in the presence of hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs. The molecular analysis of the fibroblast growth factor receptor 1 identified a heterozygous mutation c.1377_78insA (p.V460SfsX3) in exon 10 of FGFR1 gene. This mutation has not yet been reported in the literature. A theoretical review of clinical features and therapeutic approach of this syndrome is also presented.

Erythropoietic protoporphyria: a family study and report of a novel mutation in the FECH gene.

Erythropoietic protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis mostly caused by a deficient activity of the enzyme ferrochelatase (FECH), and consequent accumulation of protoporphyrin (PP) in various tissues. Clinical manifestations include a childhood onset, cutaneous photosensitivity and, sometimes, hepatobiliary disease. We report a 16-year-old male with EPP characterized by acute episodes of painful photosensitivity since early infancy, permanent changes in the photoexposed skin, microcytic anemia, thrombocytopenia, and mild hepatic dysfunction. His 18-year-old sister presented less acute symptoms with no chronic changes. Lesional biopsy disclosed perivascular deposition of PAS positive hyaline material. Rimington-Cripps test was positive and PP erythrocyte levels were >9,000 µg/L (N<1,600), but normal in their parents and younger brother. Genetic studies in both patients and their mother revealed heterozygosity for a novel mutation (c.1052delA) in FECH gene of both children, and heterozygosity for the hypomorphic allele IVS3-48T>C in all of them. This confirms the "pseudodominant" inheritance pattern usually observed, explained by the combined presence of a disabling FECH mutation and a common intronic polymorphism affecting the counterpart allele (IVS3-48T>C). Phenotypic heterogeneity for this genotype explains the divergent clinical presentation. This is the first description of a Portuguese family with EPP characterized at the molecular level.

Novel deletion encompassing exons 5-12 of the UBE3A gene in a girl with Angelman syndrome.

Angelman syndrome (AS) is characterised by severe developmental delay, severe speech impairment, gait ataxia and/or limb tremor and a unique behavioural phenotype. The diagnosis of AS is based on a combination of clinical features and molecular genetic testing. Currently, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies anomalies in about 90% of individuals. The aetiology of the remaining 10% is still unknown. We report a novel deletion encompassing the exons 5-12 of the UBE3A gene in a girl with AS, identified by MLPA (Multiplex Ligation-dependent Probe Amplification), which was not detected by the conventional diagnostic protocol. We propose that copy number analysis of the UBE3A gene should be considered in individuals whose clinical examination is strongly suggestive of AS, after more common mechanisms have been excluded.

Piebaldism and neurofibromatosis type 1: family report.

Piebaldism is a rare disorder present at birth and inherited as an autosomal dominant trait. It results from a mutation in the c-kit proto-oncogene and is associated with a defect in the migration and differentiation of melanoblasts from the neural crest. Clinical manifestations and phenotypic severity strongly correlates with the site of mutation within the KIT gene. Here we report a 3-year-old boy and his 33-year-old father with leukoderma and poliosis associated with clinical criteria for Neurofibromatosis type 1. Genetic study of both revealed a p.Gly610Asp mutation in the KIT gene. This familiar mutation has not yet been reported in the literature. There are rare reports of piebaldism in association with neurofibromatosis type I.

[Hereditary pancreatitis in a child]. / Pancreatite hereditária na criança.

Hereditary pancreatitis is defined as a family history of two or more relatives with pancreatitis and clinical, biochemical, or radiologic evidence of pancreatitis. This is the fourth family described with hereditary pancreatitis related to mutation c.364C>T (p.R122C) of PRSS1 gene. The index case was a four year old child who had had his first episode of abdominal pain at age three. At that time he was admitted in hospital for two days and he improved with analgesic treatment only. One year later, in a second similar episode, he had been diagnosed with pancreatitis. His father was submitted to pancreato-duodenectomy (Whipple procedure) when he was 27 years old due to recurrent pancreatitis since age 19. Paternal grandfather and the parents of this grandfather had been diagnosed with diabetes mellitus. The mutation R122C was present in heterozigoty, in the exon 3 of PRSS1 gene, in the index case and also in his father. The importance of a long term follow-up is highlighted, taking into consideration the risk of ductal pancreatic adenocarcinoma.

Epidermolytic hyperkeratosis with palmoplantar keratoderma in a patient with KRT10 mutation.

We report the case of a 12-year-old girl presenting at birth with erythroderma, erosions and blisters scattered over the integument. By the age of 3 she presented generalized hyperkeratotic plaques with a cobblestone pattern and a pungent odour, most prominently around flexures, scalp and palmoplantar areas. Clinical, histological and ultrastructural findings confirmed the diagnosis of epidermolytic hyperkeratosis (EHK). Molecular genetic analysis revealed a mutation in the KRT10 gene. Treatment with oral acitretin was attempted but it was discontinued due to hepatic dysfunction and marked desquamation and blistering. EHK is a rare autosomal dominant disorder of keratinization, caused by mutations in either the KRT1 or KRT10 genes. Although palmoplantar keratoderma is typically found in patients with KRT1 mutation, our patient presents EHK with palmoplantar involvement and KRT10 mutation. Moreover, a poor response to systemic retinoids was observed, contrary to what is expected in patients with KRT10 mutation. Even though management is usually unsatisfactory, some patients with this lifelong and serious condition may experience improvement with age.

Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome.

Alström syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (DCM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alström syndrome for mutations in the ALMS1 gene. In total, 79 disease-causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease.

Cúspide em garra: relato de caso clínico / Talon cusp: case report

A cúspice em garra é uma alteração de desenvolvimento da forma dentária que se caracteriza pela presença de uma cúspide acessória na face lingual ou vestibular de um dente anterior. Sua etiologia é incerta, sendo uma provável alteração na morfodiferenciação do estágio de odontogênese. O presente artigo tem como objetivo relatar um caso clínico de cúspide em garra em uma criança de 10 anos de idade e discutir formas de diagnóstico e tratamento para esta anomalia.