Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the "Cuban mutation" of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome, but do not affect lower limb development. We suggest the term "ZRS-associated syndromes" and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS.

Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.

Denosumab appears to be significantly effective for osteoclast inhibition for the treatment of JPD. However, in our patient, denosumab administration was associated with severe hypocalcemia, indicating that close monitoring of calcium levels is required during treatment.

BackgroundMutations in EFTUD2 were proven to cause a very distinct mandibulofacial dysostosis type Guion-Almeida (MFDGA, OMIM #610536). Recently, gross deletions and mutations in EFTUD2 were determined to cause syndromic esophageal atresia (EA), as well. We set forth to find further conditions caused by mutations in the EFTUD2 gene (OMIM *603892).Methods and resultsWe performed exome sequencing in two familial cases with clinical features overlapping with MFDGA and EA, but which were previously assumed to represent distinct entities, a syndrome with esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and intellectual disability in a mother and her two children [AJMG 143A(11):1135-1142, 2007] and a supposedly autosomal recessive oto-facial syndrome with midline malformations in two sisters [AJMG 132(4):398-401, 2005]. While the analysis of our exome data was in progress, a recent publication made EFTUD2 mutations highly likely in these families. This hypothesis could be confirmed with exome as well as with Sanger sequencing. Also, in three further sporadic patients, clinically overlapping to these two families, de novo mutations within EFTUD2 were identified by Sanger sequencing. Our clinical and molecular workup of the patients discloses a broad phenotypic spectrum, and describes for the first time an instance of germline mosaicism for an EFTUD2 mutation.ConclusionsThe clinical features of the eight patients described here further broaden the phenotypic spectrum caused by EFTUD2 mutations or deletions. We here show, that it not only includes mandibulofacial dysostosis type Guion-Almeida, which should be reclassified as an acrofacial dysostosis because of thumb anomalies (present in 12/35 or 34% of patients) and syndromic esophageal atresia [JMG 49(12). 737-746, 2012], but also the two new syndromes, namely oto-facial syndrome with midline malformations published by Mégarbané et al. [AJMG 132(4): 398-401, 2005] and the syndrome published by Wieczorek et al. [AJMG 143A(11): 1135-1142, 2007] The finding of mild phenotypic features in the mother of one family that could have been overlooked and the possibility of germline mosaicism in apparently healthy parents in the other family should be taken into account when counseling such families.

The PLZF gene is one of five partners fused to the retinoic acid receptor alpha in acute promyelocytic leukaemia. We describe the first patient, to our knowledge, with a germline mutation of PLZF. Our findings as well as observations in Plzf-deficient mice indicate that PLZF is a key regulator of skeletal and male germline development. Furthermore, this case highlights the importance of searching for a recessive mutation on the non-deleted chromosome in patients with a microdeletion and atypical clinical findings.

We confirm that ultrasound is an applicable and safe alternative tool to x-rays in nondisplaced or excluded metaphyseal forearm fractures in children.

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