Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis.

KBG syndrome, due to ANKRD11 alteration is characterized by developmental delay, short stature, dysmorphic facial features, and skeletal anomalies. We report a clinical and molecular study of 39 patients affected by KBG syndrome. Among them, 19 were diagnosed after the detection of a 16q24.3 deletion encompassing the ANKRD11 gene by array CGH. In the 20 remaining patients, the clinical suspicion was confirmed by the identification of an ANKRD11 mutation by direct sequencing. We present arguments to modulate the previously reported diagnostic criteria. Macrodontia should no longer be considered a mandatory feature. KBG syndrome is compatible with autonomous life in adulthood. Autism is less frequent than previously reported. We also describe new clinical findings with a potential impact on the follow-up of patients, such as precocious puberty and a case of malignancy. Most deletions remove the 5'end or the entire coding region but never extend toward 16q telomere suggesting that distal 16q deletion could be lethal. Although ANKRD11 appears to be a major gene associated with intellectual disability, KBG syndrome remains under-diagnosed. NGS-based approaches for sequencing will improve the detection of point mutations in this gene. Broad knowledge of the clinical phenotype is essential for a correct interpretation of the molecular results. © 2016 Wiley Periodicals, Inc.

BAYAT eT Al | INTRODUCTIONGlycosylphosphatidylinositol (GPI) is a glycolipid that is synthetized and transferred to proteins in the membrane of the endoplasmic reticulum. 1 Biogenesis of GPI-anchored proteins (GPI-APs) is a conserved posttranslational mechanism in eukaryotes and is important for attaching these proteins to the cell membrane and for protein sorting, trafficking, and dynamics. 1,2 GPI synthesis and GPI-AP modification are mediated by at least 31 genes, and pathogenic variants in 22 of these genes have been associated with human disease to date. 3 The X-linked phosphatidylinositol glycan class A protein gene (phosphatidylinositol glycan class A protein [PIGA]) is part of a heptameric enzyme complex catalyzing the transfer of N-acetylglucosamine (GlcNAc) to phosphatidylinositol as the first step in GPI anchor biosynthesis. [4][5][6] In contrast to other members of the GPI-GlcNAc transferase complex, PIGA is an integral membrane protein with only one transmembrane domain residing in the endoplasmic reticulum (ER). The large N-terminal cytoplasmic domain contains two Rossmann folds. 7 Pathogenic germline missense variants in PIGA are associated with multiple congenital anomalies-hypotonia-seizures syndrome 2 (OMIM 316818). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] The affected