A patient with van Maldergem syndrome with endocrine abnormalities, hypogonadotropic hypogonadism, and breast aplasia/hypoplasia

Abstract

BackgroundWe report a female patient with endocrine abnormalities, hypogonadotropic hypogonadism and amazia (breasts aplasia/hypoplasia but normal nipples and areolas) in a rare syndrome: Van Maldergem syndrome (VMS).Case presentationOur patient was first evaluated at age 4 for intellectual disability, craniofacial features, and auditory malformations. At age 15, she presented with no breast development and other findings consistent with hypogonadotropic hypogonadism. At age 37, she underwent whole exome sequencing (WES) to identify pathogenic variants. WES revealed compound heterozygous variants in DCHS1 (rs145099391:G > A, p.P197L & rs753548138:G > A, p.T2334 M) [RefSeq NM_003737.3], diagnostic of Van Maldergem syndrome (VMS-1). VMS is a rare autosomal disorder reported in only 13 patients, characterized by intellectual disability, typical craniofacial features, auditory malformations, hearing loss, skeletal and limb malformations, brain abnormalities with periventricular neuronal heterotopia and other variable anomalies. Our patient had similar phenotypic abnormalities. She also had hypogonadotropic hypogonadism and amazia. Based on the clinical findings reported, two previously published patients with VMS may also have been affected by hypogonadotropic hypogonadism, but endocrine abnormalities were not evaluated or mentioned.ConclusionThis case highlights an individual with VMS, characterized by compound heterozygous variants in DCHS1. Our observations may provide additional information on the phenotypic spectrum of VMS, including hypogonadotropic hypogonadism and amazia. However, the molecular genetic basis for endocrine anomalies observed in some VMS patients, including ours, remains unexplained.Electronic supplementary materialThe online version of this article (10.1186/s13633-017-0052-z) contains supplementary material, which is available to authorized users.

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

“…Combined with our description of expression of FAT/DCHS family members during pituitary development ( 27 ), the recent identification of links between DCHS abnormalities and pituitary developmental defects ( 8 , 23 ) suggested an involvement of FAT/DCHS signaling in hypothalamic and/or pituitary development. To address this possibility, we studied 28 patients with congenital pituitary abnormalities of EPP and/or PSIS with WES, focusing on all 4 FAT genes, as well as DCHS1 and DCHS2 .…”

“…Besides symptoms common to both syndromes, such as intellectual disability and craniofacial malformations, VMS-specific clinical symptoms include camptodactyly, syndactyly, small kidneys, osteopenia, and tracheal abnormalities ( 14 , 17 – 21 ), whereas lymphangiectasia and lymphedema are specific to Hennekam syndrome ( 17 , 18 , 22 ). A link between VMS and endocrine abnormalities, including hypogonadotropic hypogonadism and amazia, were reported in a recent study, providing new support to the possible involvement of FAT/DCHS signaling in hypothalamic-pituitary axis development or function ( 23 ). Null deletions of Fat4 or Dchs1 in mouse lead to overlapping phenotypes, including inner ear, neural tube, kidney, skeleton, lung, and heart defects ( 24 ), further supporting that these protocadherins act as a ligand-receptor pair.…”

“…Our data suggest a requirement for FAT and DCHS protocadherins in the infundibulum and mesenchyme surrounding the developing gland during morphogenesis, revealing that FAT/DCHS function is necessary for normal pituitary morphogenesis and their dysfunction can underlie developmental anomalies of the hypothalamic-pituitary axis. (27), the recent identification of links between DCHS abnormalities and pituitary developmental defects (8,23) suggested an involvement of FAT/DCHS signaling in hypothalamic and/or pituitary development. To address this possibility, we studied 28 patients with congenital pituitary abnormalities of EPP and/or PSIS with WES, focusing on all 4 FAT genes, as well as DCHS1 and DCHS2.…”

Coexistence of genetic conditions: Exploring a possible relationship

“…There are no known genetic or somatic associations between VMLDS and CAH apart from the anatomical proximity of the adrenal glands to the kidneys, and the latter could be affected in VMLDS. Few cases of VMLDS were reported with gonadal abnormalities, including hypogonadotropic hypogonadism and breast aplasia/hypoplasia in one female patient [7].…”

Spatio-temporal regulation of Dachsous proteins duringDrosophiladevelopment

“…During Drosophila development, ds is expressed in multiple cell types and its loss of function results in early lethality and abnormal size and shape of different embryonic and larval tissues such as the tracheal system (Chung et al, 2009), gut [Gonzalez-Morales et al 2015], peripheral and central nervous system (Dearborn and Kunes, 2004); (Fabre et al, 2008) and imaginal discs (Rawls et al, 2002); (Rodriguez, 2004); (Bando et al, 2009). Furthermore, mutations in the DCHS1 gene, the human homologue of ds, cause severe congenital malformations due to a global impairment in development affecting the normal formation of many tissues and organs including craniofacial, skeletal and limb malformations, hearing loss and heart valve and brain abnormalities suggesting that the altered expression of DCHS1 by diverse polymorphisms can affect in a tissue--specific and developmentally specific manner (Cappello et al, 2013); (Sotos et al, 2017); (Clemenceau et al, 2017); (Zwaveling-Soonawala et al, 2018). The ds gene was initially identified as a member of the cadherin superfamily that controls the establishment of Planar Cell Polarity (PCP), a general mechanism required for tissue organization and organ formation (Clark et al, 1995).…”