Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOX10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOX10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Objective To improve life expectancy and prevent premature mortality in women with Marfan's syndrome. Methods During the development of a regional genetic register for Marfan's Syndrome the outcome of 91 pregnancies in 36 women with this condition was established retrospectively and the cardiovascular and obstetric complications documented. Results No patient had a significant cardiovascular abnormality limiting function before her pregnancy. Of 36 women, four had an aortic dissection relating to pregnancy and two others required aortic surgery following delivery. Thirty women had uncomplicated gestational histories. The incidence of obstetric complications did not exceed expectation. Conclusions Women with Marfan's syndrome are at significant risk of aortic dissection in pregnancy even in the absence of preconceptional cardiovascular abnormality. Aortic root dilatation may be a predictor of risk but dissection may occur without significant dilatation. Guidelines for obstetric care are suggested and preconceptional assessment recommended.

Introduction The Australasian Society of Clinical Immunology and Allergy, the peak professional body for clinical immunology and allergy in Australia and New Zealand, develops and provides information on a wide range of immune‐mediated disorders, including advice about infant feeding and allergy prevention for health professionals and families. Guidelines for infant feeding and early onset allergy prevention were published in 2016, with additional guidance published in 2017 and 2018, based on emerging evidence. Main recommendations When the infant is ready, at around 6 months, but not before 4 months, start to introduce a variety of solid foods. (This is not a strict window of introduction but rather a recommendation not to delay the introduction of solid foods beyond 12 months.) Introduce peanut and egg in the first year of life in all infants, regardless of their allergy risk factors. Hydrolysed (partially and extensively) formula is no longer recommended for the prevention of allergic disease. Changes in management a result of the guidelines The guidelines specifically recommend introducing solid foods at around 6 months of age and introducing peanut and egg in the first year of life in all infants to prevent allergy development. Hydrolysed formula is no longer recommended for prevention of allergic disease. A new document outlining the reasons for and the method of peanut introduction to high risk infants is available for health professionals.