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.

No abstract

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.

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.

RESUMO -A protoporfiria eritropoiética (PPE), é uma genodermatose rara causada, na maioria dos doentes, pela redução da actividade da ferroquelatase (FECH), a última enzima da biossíntese do heme, e consequente acumulação de protoporfirina (PP) em vários tecidos. Os autores descrevem um adolescente de 16 anos (caso índice) que sofria de PPE desde a infância, caracterizada por episódios agudos de fotossensibilidade dolorosa nas áreas foto-expostas, alterações crónicas, anemia microcítica, trombocitopenia e disfunção hepática ligeira. A irmã de 18 anos apresentava sintomas agudos mais ligeiros e não evidenciava alterações crónicas. Os progenitores e o irmão mais novo eram assintomáticos. A biópsia lesional efectuada no caso índice mostrou deposição de material hialino, PAS-positivo, em localização perivascular. O teste de Rimington-Cripps foi positivo em ambos os doentes sintomáticos e os níveis de PPs eritrocitárias encontravam-se elevados, mas normais nos pais e no irmão mais novo. O estudo genético, efectuado em ambos os doentes e na mãe (amostra do pai não disponível por paradeiro desconhecido), revelou heterozigotia para uma nova mutação no gene FECH (c.1052delA) nos filhos e heterozigotia para o alelo hipomórfico IVS3-48T>C em todos os elementos testados. Confirmou-se, assim, o padrão de hereditariedade "pseudodominante" observado na maioria das famílias, explicado pela presença simultânea de uma mutação no gene FECH e de um polimorfismo frequente, afectando o alelo oposto (IVS3-48T>C). Neste caso, o alelo mutante foi provavelmente herdado do pai. Do nosso conhecimento, esta é a primeira descrição de uma família portuguesa com PPE caracterizada do ponto de vista molecular, tendo-se descrito uma nova mutação, não referida na literatura.

No abstract

No abstract

SummaryThe 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. BACKGROUND