טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentGenser-Nir Mira
SubjectJuvenile Hypertrophy of The Breast (JHB) Accompanied by
Familial Onychodysplasia and Dysplasia of Distal
Phalanges (ODP): Mapping of a Novel
Genetic Syndrome
DepartmentDepartment of Medicine
Supervisor Ms. Tzipora Falik
Full Thesis text - in Hebrew Full thesis text - Hebrew Version


Abstract

We report a five-generation Druze family with a novel phenotypic association consisting of anonychia-onychodystrophy with hypoplasia or absence of distal phalanges (ODP) in males and females, accompanied by juvenile hypertrophy of the breast (JHB) in affected females. We named this syndrome Mammary, Digital and Nails (MDN) syndrome for the main tissues that are involved in its phenotype.

The genetic basis of MDN is unclear. Moreover, the normal developmental and biochemical processes involved in growth and development of the distal bones and nails in hands and feet, as well as breast development in healthy girls, are not fully understood.

A genome-wide screening was performed under both AR (99% penetrance) and AD (50%-100% penetrance). MDN syndrome was mapped to chromosome 22q12.3-13.1 with a maximum LOD score of 4.3 at three out of six continuous linked markers, under AD inheritance with full penetrance. AR inheritance was ruled out for MDN.  Haplotype analysis revealed a common haplotype among all the eleven affected individuals originated by extrapolation from the deceased healthy founder father II4 and encompassing a 12cM interval (4.3Mb). This chromosomal region has not been previously implicated in genetic disorders of the mammary tissue and/or limbs. The mode of inheritance suggests autosomal dominant (AD), with either partial penetrance or germinal mosaicism (GM). We investigated the possibilities of di-genic inheritance and a modifier gene responsible for the novel phenotype. However, we did not identify a second locus that might be involved in the inheritance of this phenotype. The pedigree and the haplotype data that co-segregates with the disease, but was found also in nine healthy individuals in the pedigree firmly confirm the possibility of a GM event in the founder healthy father (II4).

Sequencing of 38 candidate genes within the linked interval that might be involved in the known signaling pathways of limbs and mammary glands during mammalian embryogenesis did not reveal a disease-causing sequence alteration.

Considered together with previous observations of clinical associations between abnormal limbs and breast development, the present data suggest a new genetic syndrome, mammary-digital-nail (MDN) syndrome and a possible novel-signaling pathway affecting the organogenesis of limbs and mammary glands in humans. Unraveling the challenge presented by this novel syndrome may elucidate mechanisms of normal growth and development of the tissues involved, a common biochemical pathway of the two traits, and the genetic basis for the association between JHB and ODP.