Severe Bartter syndrome type 1: Prompt postnatal management thanks to antenatal identification of SLC12A1 pathogenic variants.

Bartter syndrome (BS) refers to a group of hereditary kidney disorders. One antenatal form is Bartter syndrome type 1 (BS1), caused by pathogenic variants in the SLC12A1 gene. We report a case of BS1 presenting with severe polyhydramnios. The fetus was found to carry three pathogenic variants of SLC12A1, leading to the antenatal diagnosis of BS1 and its prompt management. At age 18 days, clinical conditions were complicated by the onset of sepsis requiring supportive measures as well as steroid and antibiotic therapy. Any newborn with an antenatal history of polyhydramnios or postnatal polyuria should be suspected of having BS, since delayed diagnosis may lead to rapid renal failure.

Congenital heart defects in the recurrent 2q13 deletion syndrome.

The recurrent 2q13 deletion syndrome is a rare genetic disorder associated with developmental delay, cardiac and urogenital malformations, and minor facial anomalies. Congenital heart defects (CHDs) are the most frequent malformations associated with del2q13. Experimental studies in zebrafish suggest that two genes mapping within the 2q13 critical region (FBLN7 and TMEM87B) could confer susceptibility to congenital heart defects in affected individuals. We reviewed the cardiac characteristics in four patients with 2q13 deletion admitted to our hospitals, and in published patients. Two of our patients had congenital heart defects, consisting in partial anomalous pulmonary venous connection, ostium secundum atrial septal defect ostium secundum, and small muscular ventricular septal defect in one of them, and aortic valve insufficiency with partial fusion of two commissures (incomplete bicuspid aortic valve) and mitral valve insufficiency due to trivial mitral valve prolapse in the other. The anatomic types of CHD in del2q13 syndrome are highly variable and distributed widely, including laterality defects, complex atrioventricular septal defect, septal anomalies, and cardiomyopathies. Cardiac evaluation should be part of the clinical workup at diagnosis of 2q13 deletion.

A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy.

OBJECTIVES: Homozygous mutations in HPGD gene, encoding 15-hydroxyprostaglandin dehydrogenase, have recently been associated with primary hypertrophic osteoarthropathy (PHO). So far, only 7 HPGD alterations are known. In order to expand this mutational spectrum and better delineate the HPGD-related phenotype, we report the clinical and molecular characterisation of a 13-year-old boy and compare his features to known mutated patients. METHODS: The HPGD gene exons 1-7 and exon-intron junctions were analysed by direct sequencing. Previously published HPGD-mutated patients were systematically reviewed based on the original clinical description. RESULTS: A novel homozygous c.217+1G>A mutation affecting the obligatory donor splice site of HPGD exon 2 was identified in our proband who showed a mild form of PHO. Review of HPGD-mutated patients outlined all patients manifested digital clubbing, periostosis and acro-osteolysis. Hyperhidrosis (92%), arthralgia (65%) and eczema (33%) were variably associated features. Pachydermia (54%) was mild and mostly limited to palms and sole; cutis vertigis gyrata, blepharoptosis and severe skin thickening were never observed. Besides digital clubbing, PHO infants often presented patent ductus arteriosus (PDA) (32%) and delayed cranial sutures closure (55%). CONCLUSIONS: The present findings broaden the allelic spectrum of HPGD gene to include a novel c.217+1G>A mutation. Mutated patients display a homogeneous phenotype mainly consisting in digital clubbing, periostosis, acro-osteolysis, hyperhidrosis and mild pachydermia. Earliest manifestations include delayed closure of the cranial sutures and PDA. In conclusion, the information reported herein would facilitate the diagnosis of PHO due to HPGD mutations.

Triple A syndrome: a novel compound heterozygous mutation in the AAAS gene in an Italian patient without adrenal insufficiency.

Allgrove syndrome (or triple A syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency and autonomic/neurological abnormalities. It is caused by mutations in the AAAS gene, located on chromosome 12q13. We describe a 42-year-old patient who presented with neuropathy and was found to have alacrima, achalasia, mild autonomic dysfunction with significant central and peripheral nervous system involvement. She was later diagnosed with oligosymptomatic triple A syndrome. Sequencing of the AAAS gene identified two heterozygous mutations within exon 14 and its donor splice site (p.L430F-c.1288C>T and c.1331+1G>T), one of which is novel. Allgrove syndrome should be suspected in patients with neurological impairment associated with two or more of the main symptoms (alacrima, achalasia or adrenal insufficiency).

Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification.

To estimate the contribution of single and multi-exon NF1 gene copy-number changes to the NF1 mutation spectrum, we analysed a series of 201 Italian patients with neurofibromatosis type 1 (NF1). Of these, 138 had previously been found, using denaturing high-performance liquid chromatography or protein truncation test, to be heterozygous for intragenic NF1 point mutations/deletions/insertions, and were excluded from this analysis. The remaining 63 patients were analysed using multiplex ligation-dependent probe amplification (MLPA), which allows detection of deletions or duplications encompassing >or=1 NF1 exons, as well as entire gene deletions. MLPA results were validated using real-time quantitative PCR (qPCR) or fluorescent in situ hybridisation. MLPA screening followed by real-time qPCR detected a total of 23 deletions. Of these deletions, six were single exon, eight were multi-exon, and nine were of the entire NF1 gene. In our series, deletions encompassing >or=1 NF1 exons accounted for approximately 7% (14/201) of the NF1 gene mutation spectrum, suggesting that screening for these should now be systematically included in genetic testing of patients with NF1.