A prenatally recognizable malformation syndrome associated with a recurrent post‐zygotic chromosome rearrangement der(Y)t(Y;1)(q12:q21)

Abstract

Several cases of mos 46,X,der(Y)t(Y;1)(q12;q21)/46,XY with multiple anomalies have been reported. I report on an additional case of a male fetus with a mosaic male karyotype mos 46,X,der(Y)t(Y;1)(q12;q21)[31]/46,XY[21] and multiple anomalies that included "teardrop"-shaped head with a triangular face, a short-nasal bridge with upturned nose, microretrognathia, microtia, kyphoscoliosis, oligodactyly, syndactyly, joint contractures, CNS malformation, omphalocele, diaphragmatic hernia, cardiac anomaly, and urogenital malformation. The findings together suggest a recurrent and recognizable syndrome and argue for using tissues such as skin or cartilage or amniotic fluid, instead of cord blood, for postmortem karyotyping in order to avoid missing mosaicism as a potential cause of multiple congenital anomalies.

Microtia: Epidemiology and genetics

“…Chromosomal translocations involving the 6p24 region have been associated with orofacial clefting and bilateral microtia [Davies et al, 1998]. Several cases reports of mosaicism 46,X,der(Y)t(Y;1)(q12;q21)/46,XY describe the presence of microtia associated with anomalies such as kyphoscoliosis, oligodactyly, joint contractures, central nervous system malformations, omphalocele, diaphragmatic hernia, cardiac defects, and urogenital malformation [Watson et al, 1990; Zeng et al, 2003; Scheuerle et al, 2005; Li, 2010]. Microtia has been associated with abnormalities in each of the chromosomes [POSSUM, 2010] confirming Schinzel's [2001] observation that malformations confined to one or very few chromosome aberrations are suspicious for single gene deletions, whereas, malformations frequent in chromosome aberrations are caused by deficiency of a step in organogenesis.…”

Mosaic trisomy 1q: a recurring chromosome anomaly that is a diagnostic challenge and is associated with a Fryns-like phenotype

“…Trisomy of the entire long arm of chromosome 1 as the sole imbalance is an exceedingly rare chromosomal abnormality, with 12 cases reported in the literature . The majority of cases result from an unbalanced translocation between chromosome 1 and either chromosome Y or an acrocentric chromosome.…”

“…Whole‐arm trisomy 1q in association with an unbalanced translocation with the Y chromosome, 46,X,der(Y)t(Y;1)(q12;q21) or 46,X,der(Y)t(Y;1)(q12;q21) (1q12 and 1q21 are adjacent bands on the proximal long arm of chromosome 1), has been described seven times in the literature . The breakpoint on the Y chromosome has been consistently in the heterochromatic region, resulting in the loss of only Y heterochromatic material and considered of no clinical significance.…”

“…All of the ten prenatally diagnosed cases had multiple congenital anomalies, including elevated first‐trimester nuchal translucency, congenital diaphragmatic hernia, omphalocele, brain anomalies and cystic kidneys . Other common prenatal or post‐natal features included microphthalmia; anomalies of the brain such as ventriculomegaly, agenesis of the corpus callosum and cerebellar vermis hypoplasia; and hand abnormalities including camptodactyly, syndactyly, abnormally placed digits and hypoplastic nails.…”

“…Based on this constellation of anomalies, several of the cases with mosaic trisomy 1q cases were initially suspected of having Fryns syndrome because of the presence of a congenital diaphragmatic hernia and nail hypoplasia . Fryns syndrome is diagnosed based on clinical findings, and a comprehensive review of published cases concluded that diaphragmatic defects, such as congenital diaphragmatic hernias and distal limb hypoplasia, including nail hypoplasia, were strongly suggestive of Fryns syndrome .…”