Transient Bullous Dermolysis of the Newborn

DEBRA International (DI) is undertaking a long-term initiative to develop Clinical Practice Guidelines (CPGs) for Epidermolysis Bullosa (EB), to improve the clinical care of people living with EB. Current neonatal care is based on evidence, clinical expertise and trial and error with collaboration between the EB specialist team, parent/carer and patient, and is dependent on the neonate's individual presentation and type of EB. Early intervention based on research and clinical practice, is needed to establish a foundation of knowledge to guide international practitioners to create and improve standards of care and to be able to work effectively with those newly diagnosed with EB. This CPG was created by an international panel with expertise working with persons with EB. The CPG focuses on neonatal care using a systematic review methodology covering four key areas. Diagnosis and parent psychosocial supportHospital management: medical monitoring, wound care, and painFeeding and nutritionDischarge planning and EB Education These four areas highlight the importance of a multidisciplinary team (MDT) approach, to provide a patient-specific holistic care model that incorporates the needs and wishes of the parents/carers. The hospital implementation tool included promotes transfer of theory to clinical practice.

Epidermolysis Bullosa (EB) is a heterogeneous group of congenital blistering diseases that usually presents in the neonatal period. EB is classified into three major categories, each with many subtypes based on the precise location at which separation or blistering occurs, namely epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB) and dystrophic epidermolysis bullosa (DEB). We describe genetics of neonatal EB in Hong Kong. Two neonates of consanguineous Pakistani parents had the EB-Pyloric Atresia (EB-PA) variant. One had a 4 kb homozygous deletion of exon 19-25 of the ITGB4 gene, and the other with only a histopathological diagnosis. Both died of sepsis in infancy. Aberrant COL7A1 mutations in the dominant and recessive EB were described. Genetic analysis, together with histopathological classification is important to aid prognosis and counselling. JEB and EB-PA are associated with consanguinity and mortality during infancy. Morbidity and prognosis of the autosomal dominant DEB is optimistic. The autosomal recessive DEB is more severe, with neonatal onset and recurrent blistering. It is also associated with chronicity and malignant changes when the child reaches adulthood. Exact genetic diagnosis aids in counselling of the family concerning the prognosis in the affected child and the risk of affected children in future pregnancies.

Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified.

To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP.

We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo.

A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 × 10-5). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1+/- and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/- mice despite normal postnatal growth.

We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.