20p11 deletion in a female child with panhypopituitarism, cleft lip and palate, dysmorphic facial features, global developmental delay and seizure disorder

Abstract

Deletions of 20p are rare with the majority of reported cases involving individuals with 20p12 deletions associated with Alagille syndrome. We report on a child with a de novo mosaic 20p11 deletion who presents with panhypopituitarism; hypoplastic pituitary gland and ectopic posterior pituitary gland on MRI of the brain; cleft lip and palate; kyphosis with anterior beaking of L1 and L2 vertebral bodies; pulmonic stenosis; dysmorphic facial features including flat nasal bridge, hypoplastic premaxilla, hypotelorism, preauricular pit, and cupped ears; seizure disorder; variable muscle tone; and global developmental delay. Array comparative genomic hybridization revealed this deletion to be approximately 5.4 Mb in size, containing 35 genes. Previously, an infant with 20p11.22 deletion who had panhypopituitarism, craniofacial, and genital abnormalities was reported, but the precise parameters of that deletion are unavailable. Several other reported cases of 20p11 deletions also have phenotypic overlap with our case. The similarities in clinical features of these patients suggest that the genes at 20p11 have a critical role in development of midline brain structures.

Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome

“…Heterotaxy has been reported in at least three other patients with 20p11.2 deletions that include FOXA2 (Kale et al, ; Tsai et al, ) and is not reported in patients where FOXA2 is not deleted (Figure b, Kamath 2009 Pt 19 and Pt 21; Table SII). Other midline defects most frequently described were structural or functional pituitary anomalies (e.g., panhypopituitarism), seen in 5 of the 7 previously reported patients in whom this feature was specified (Table SI) (Dayem‐Quere et al, ; Garcia‐Heras et al, ; Kale et al, ; Kamath et al, ; Williams et al, ). Additional midline defects include a paramedian cleft lip and palate reported in one patient with a 20p11.2 deletion (Williams et al, ).…”

“…Other midline defects most frequently described were structural or functional pituitary anomalies (e.g., panhypopituitarism), seen in 5 of the 7 previously reported patients in whom this feature was specified (Table SI) (Dayem‐Quere et al, ; Garcia‐Heras et al, ; Kale et al, ; Kamath et al, ; Williams et al, ). Additional midline defects include a paramedian cleft lip and palate reported in one patient with a 20p11.2 deletion (Williams et al, ). Dayem‐Quere and colleagues proposed a region of approximately 1.35 Mb ([GRCh37] chr20:22,303,261‐23,652,145) that includes FOXA2 as the critical region associated with hypopituitarism and/or growth hormone deficiency (Dayem‐Quere et al, ).…”

“…Chromosome 20p deletions are rare and associated with a wide variety of anatomical and developmental abnormalities. Proximal deletions of 20p11.2 have been reported to cause a variable phenotype that includes heterotaxy, biliary atresia, panhypopituitarism, midline defects, intellectual disability, scoliosis, and seizures (Dayem‐Quere et al, ; Garcia‐Heras, Kilani, Martin, & Lamp, ; Kale, Patil, & Pandit, ; McGaughran, Oates, Donnai, Read, & Tassabehji, ; Michaelis et al, ; Tsai et al, ; Williams, Wetherbee, Rosenfeld, & Hersh, ). The size of these reported 20p11.2 deletions ranges from 277 kb to 11.96 Mb.…”

Heterozygous Deletion ofFOXA2Segregates with Disease in a Family with Heterotaxy, Panhypopituitarism, and Biliary Atresia

“…Proximal deletions of 20p11 are rare. Four patients with 20p deletions of varying sizes, which include FOXA2 have been previously reported in the literature [Garcia‐Heras et al., ; Kamath et al., ; Williams et al., ; Dayem‐Quere et al., ], and their reported symptoms include intellectual disability, developmental delay, seizures, panhypopituitarism, and facial dysmorphism [Dayem‐Quere et al., ]. Three of the four patients had panhypopituitarism while the remaining patient had an empty sella and presented with growth hormone deficiency.…”

Heterozygous defects in PAX6 gene and congenital hypopituitarism

“…Several cases of CH with submicroscopic chromosomal rearrangements, such as 20p11 deletions and 22q12.3q13.3 duplication, whose definitive causative genes responsible for CH are not fully captured, have been reported (6,7,8). These patients were syndromic and showed extra pituitary clinical spectra, including dysmorphic faces, midline defects, and intellectual disability.…”