Homozygous truncating PTPRF mutation causes athelia

Abstract

Athelia is a very rare entity that is defined by the absence of the nipple-areola complex. It can affect either sex and is mostly part of syndromes including other congenital or ectodermal anomalies, such as limb-mammary syndrome, scalp-ear-nipple syndrome, or ectodermal dysplasias. Here, we report on three children from two branches of an extended consanguineous Israeli Arab family, a girl and two boys, who presented with a spectrum of nipple anomalies ranging from unilateral hypothelia to bilateral athelia but no other consistently associated anomalies except a characteristic eyebrow shape. Using homozygosity mapping after single nucleotide polymorphism (SNP) array genotyping and candidate gene sequencing we identified a homozygous frameshift mutation in PTPRF as the likely cause of nipple anomalies in this family. PTPRF encodes a receptor-type protein phosphatase that localizes to adherens junctions and may be involved in the regulation of epithelial cell-cell contacts, peptide growth factor signaling, and the canonical Wnt pathway. Together with previous reports on female mutant Ptprf mice, which have a lactation defect, and disruption of one allele of PTPRF by a balanced translocation in a woman with amastia, our results indicate a key role for PTPRF in the development of the nipple-areola region.

Phenotypic expansion of KMT2D‐related disorder: Beyond Kabuki syndrome

“…Additional genes that are associated with abnormal breast development include: (a) TBX3 , which causes Ulnar‐Mammary syndrome (MIM 181450) (M. Bamshad et al, ); (b) TP63 which causes multiple developmental disorders (M. J. Bamshad, ; Rinne, Hamel, van Bokhoven, & Brunner, ); (c) EDA , which causes X‐Linked Hypohidrotic Ectodermal Dysplasia (XLHED) (MIM 305100) (Wahlbuhl‐Becker, Faschingbauer, Beckmann, & Schneider, ); (d) EDAR , which causes autosomal recessive hypohidrotic ectodermal dysplasia (MIM 224900) (Haghighi et al, ); and (e) Figure , which causes Yunis–Varon syndrome (MIM 216340) (Campeau et al, ). Two families with variants that disrupt PTPRF have been reported to have athelia (MIM 616001) (Ausavarat et al, ; Borck et al, ). Ausavarat et al, is supplemented with a summary of 62 other cases with absent breast tissue/nipples, most of which are molecularly undefined.…”

KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors

“…Interestingly the phenotype observed in KCTD1 mutated SEN patients does not appear to be due only to alteration of the AP2α signaling but is likely to be associated to alteration of other signalling. Indeed, athelia has been associated also to alterations in the WNT signalling [41] . Likewise, anomalies in the Hh pathway, may lead to a pattern of developmental defect that partially overlap with the SEN syndrome.…”

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

“…The only genetic abnormalities reported in patients with aplasia or hypoplasia of the breasts or nipples were the following: An 18 years old female with a homozygous mutation on the ligand domain of the ESR1, gene, rendering the ESR1 functionally inactive, who had amastia and infertility [ 28 ]. Two siblings and a cousin who had unilateral or bilateral athelia with a homozygous mutation in the PTPRF gene (protein tyrosine phosphatase receptor type F) in chromosome 1p32.2 [ 29 ]. The PTPRF gene (also called the Leukocyte Antigen-Related Tyrosine phosphatase or LAR gene) encodes a membrane protein.…”

“…Two siblings and a cousin who had unilateral or bilateral athelia with a homozygous mutation in the PTPRF gene (protein tyrosine phosphatase receptor type F) in chromosome 1p32.2 [ 29 ]. The PTPRF gene (also called the Leukocyte Antigen-Related Tyrosine phosphatase or LAR gene) encodes a membrane protein.…”