Endocrine Abstracts

Advances in DNA sequencing technology have provided insights into the genomic architecture of rare disorders, including DSDs. Genomic testing in clinical setting is now accessible for NHS patients, and we present a series of examples from our regional DSD service of patients and families highlighting the complexity in this field and the role of a clinical geneticist in the diagnostic pathway. A 3.5-year-old girl with clinical diagnosis and family history of CAIS had analysis of the R146 DSD gene panel, which did not identify an AR variant. Clinical suspicion of an unusual AR variant was confirmed on bespoke genome sequencing which showed a 6kb deletion involving the promoter sequence and part of exon1 of AR, likely causing loss of expression of the androgen receptor. This is a novel molecular mechanism causing androgen insensitivity. Three brothers with variable degree of hypospadias, and history of suggestive problems in maternal relatives, were shown to have a loss-of-function variant in MAMLD1, an X-linked cause of hypospadias. Prospective follow-up of these siblings has provided unique insights into the natural history of this rare disorder. A 14-year-old girl presented with signs of virilisation from a testosterone secreting left-sided gonadoblastoma. Urgent analysis of the DSD gene panel showed a pathogenic variant in MAP3K1, which causes gonadal dysgenesis. This facilitated appropriate management, including contralateral gonadectomy. We will also present the clinical and genomic data on patients with less common DSDs including Leydig cell hypoplasia, true isolated 17,20 lyase deficiency, and sex-reversal from WT1-related Frasier syndrome. Genital anomalies might be a clue to the diagnosis of a rare multisystem syndrome. We will illustrate this through patients who have been diagnosed with KAT6B-related Lin-Gettig syndrome, 17q12 deletion related Mayer-Rokitansky-Kuster-Hauser, ARX-related epileptic encephalopathy, and PAGOD (pulmonary hypoplasia, agonadism, omphalocele, diaphragmatic defect and dextrocardia) syndrome. Lastly, we have seen two children with 46,XY DSD manifesting as sex reversal have been seen in the context of a rare genomic disorder which is not associated with DSD. One is a 4.5-year-old 46,XY girl with WDR73-related Galloway-Mowat syndrome and the second patient is a 2.5-year-old 46,XY girl a1.3Mb deletion at 19p13.3, including the ZBTB7A gene.