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Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Hartsfield syndrome has been recently reported to be associated with mutations in FGFR1 however, to this date; no familial cases have been reported. In this report, we describe two siblings with Hartsfield syndrome and a novel de novo FGFR1 mutation suggesting gonadal mosaicism. The proband presented at our institution at age 6 years with a clinical diagnosis of Hartsfield syndrome and requesting further genetic evaluation. Previous studies included a normal karyotype, oligonucleotide array, and single gene testing for nonsyndromic holoprosencephaly (SHH, SIX3, ZIC2, TGIF). At the age of 6 years, exome sequencing was performed and a de novo novel missense variant was identified in FGFR1 (coding for fibroblast growth factor-1) on chromosome 8p12: c.1880G>C (p.R627T). Subsequently, a younger sibling was born with the same phenotype (holoprosencephaly, ectrodactyly of bilateral hands and feet and bilateral cleft lip and palate). Targeted sequencing of FGFR1 revealed the identical variant that was previously identified in the proband. To our knowledge this observation is the first documentation of familial recurrence of Hartsfield syndrome. As both parents were negative for the sequence variant in FGFR1 gene by testing peripheral blood samples, this suggests gonadal mosaicism. The frequency of gonadal mosaicism in Hartsfield syndrome is not known however given our case, this possibility should be taken in to consideration for recurrence risk estimation in children of clinically unaffected parents., (© 2014 Wiley Periodicals, Inc.)

We report on a father and his 4-year-old son sharing a characteristic dysmorphic facial phenotype (including hyperteleroism, prominent forehead, and wide nasal bridge), macrocephaly, hearing loss, palatal clefting, developmental delay, hypotonia and bony abnormalities including marked cranial sclerosis and sclerosis of the ribs and long bones, which evolved in severity in the son between the ages of 2 and 4 years. The father's radiographs also showed prominent coarse striations, patchy metaphyseal sclerotic plaques, markedly increased bone density and cortical thickening of long bones, and significant degenerative changes in the thoracic spine. The son has an additional history of sleep apnea resulting from multi-level airway obstruction that includes adenoid hypertrophy, lingual tonsil hypertrophy, subglottic stenosis, and supra-arytenoid tissue consistent with laryngomalacia and tracheomalacia. The clinical, radiographic, and genetic findings in father and son are consistent with a sclerosing skeletal dysplasia syndrome with similarities to mixed sclerosing bone dysplasia (MSBD) including metaphyseal plaques, osteopathia striata, and cranial sclerosis (OS-CS). This family may represent one of the first descriptions of familial inheritance and evolving phenotype in MSBD. The evidence for male-male transmission would support the existence of an autosomal mechanism of inheritance for a novel form of MSBD with characteristic syndromic features., (Copyright © 2012 Wiley Periodicals, Inc.)

Cornelia de Lange Syndrome (CdLS) is a genetically heterogeneous disorder characterized by dysmorphic facial features, cleft palate, limb defects, growth retardation, and developmental delay. Approximately 60% of patients with CdLS have an identifiable mutation in the NIPBL gene at 5p13.2. Recently, an X-linked form of CdLS with a generally milder phenotype was attributed to mutation of the structural maintenance of chromosomes 1A gene (SMC1A) at Xp11.22. Relatively few CdLS patients with mutations in SMC1A are known; female carriers have minor facial dysmorphism and cognitive deficiency without major structural abnormalities. To date, all mutations identified in SMC1A are missense or small in-frame deletions that preserve the open reading frame of the gene and likely have a dominant-negative effect. We report on a female with monosomy X mosaicism and a phenotype suggestive of a severe form of CdLS who presented with growth and mental retardation, multiple congenital anomalies, and facial dysmorphism. Array CGH confirmed mosaic monosomy X and identified a novel deletion of SMC1A spanning multiple exons, suggesting a possible loss-of-function effect. Sequencing of both genomic and cDNA demonstrated an 8,152 bp deletion of genomic DNA from exon 13 to intron 16. Although a loss-of-function effect cannot be excluded, the resulting mRNA remains in-frame and is expressed in peripheral blood lymphocytes, suggesting a dominant-negative effect. We hypothesize that the size of this deletion compared to previously reported mutations may account for this patient's severe CdLS phenotype. The presence of mosaic monosomy X may also modify the phenotype., (Copyright © 2011 Wiley Periodicals, Inc.)

We report on a male infant with otopalatodigital syndrome type 2 (OPD2) associated with a novel c.514C>G FLNA mutation and unusual clinical features including bifid tongue and congenital corneal clouding. Bifid tongue and congenital corneal clouding have each only been described once previously in a patient with OPD2, and this is the first description of Dandy-Walker malformation (DWM) in OPD2. The presence of these clinical findings in a mutation-confirmed case of OPD2 supports the notion that corneal clouding, bifid tongue, and DWM are part of the constellation of abnormalities caused by mutations in FLNA., (Copyright © 2011 Wiley-Liss, Inc.)

Juvenile polyposis syndrome (JPS) is a hereditary condition characterized by development of gastrointestinal polyps, and caused by mutations in SMAD4 or BMPR1A genes. Juvenile polyps can also be found in a related group of syndromes with multisystemic involvement including Cowden disease, Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndrome, all grouped as PTEN hamartoma tumor syndromes (PHTS). In all these conditions including JPS, polyps manifest in older childhood or early adulthood. Infantile juvenile polyposis (JPI) is a rare entity, presenting in the first year of life with severe gastrointestinal symptoms. Many of these patients have associated macrocephaly, hypotonia, and congenital anomalies. It was recently recognized that patients with infantile polyposis have a 10q23 microdeletion, involving both BMPR1A and PTEN genes. There is a major risk for gastrointestinal malignancies in these patients, but the risk for development of other tumors is not known. We describe a patient with a history of infantile polyposis, macrocephaly, developmental delay, hypotonia, and a 10q23 microdeletion. At age 14 she presented with bilateral mucinous cystadenoma of the ovary. This type of tumor was not previously reported in association with JPS, 10q23 microdeletion syndrome, or infantile polyposis. We believe that ovarian cystadenomas may be another neoplastic complication of infantile polyposis, and that our report widens the spectrum of the 10q23 microdeletion phenotype., (Copyright © 2010 Wiley-Liss, Inc.)

Feingold syndrome is a rare autosomal dominant condition that is characterized by variable expressivity of microcephaly, limb malformations, esophageal atresia, and a host of other malformations. This syndrome results from mutations in the MYCN proto-oncogene. Few examples of cross-sectional imaging of the brain in these patients are found in the literature. We present a patient who was found to have areas of cerebral and cerebellar white matter hyperintensity with T2 weighted magnetic resonance (MR) imaging. To the best of our knowledge, this finding has not been previously described. While the significance and pathologic basis of this finding are unknown, its recognition is important since it has potential to be confused with imaging findings in other conditions. Moreover, it is likely to be observed in the future due to increased use of MR imaging.

PAGOD syndrome is a rare condition characterized by multiple congenital anomalies including pulmonary artery and lung hypoplasia, agonadism, diaphragmatic abnormalities, cardiac defects, omphalocele, and various genital anomalies. The etiology of this condition is unknown but the spectrum of birth defects is similar to the developmental anomalies observed in vitamin A deficiency animal models. We describe an infant with PAGOD syndrome phenotype. The patient had a normal male karyotype and no copy number changes were seen on chromosome genomic hybridization (CGH) microarray. Endocrine evaluation was consistent with primary hypogonadism. The testes and Müllerian structures were absent by imaging studies, raising the possibility of arrest of early gonadogenesis. The plasma free vitamin A was low, consistent with moderate to severe vitamin A deficiency; the maternal plasma vitamin A level was normal. During pregnancy maternal vitamin A is taken up by retinol binding protein 4 (RBP4) which is expressed in the embryonic visceral endoderm from pregastrulational stages. This transport is mediated via the specific membrane receptor for RBP, stimulated by retinoic acid 6 (STRA6). STRA6 is widely expressed in human organ systems including the placenta during embryonic development. Mutations in the STRA6 gene result in Matthew-Wood syndrome, which demonstrates significant phenotypic overlap with PAGOD syndrome. Sequencing of STRA6 coding regions in our patient, revealed no mutations. We present a case of PAGOD syndrome with a review of the literature, posing the hypothesis that a vitamin A metabolic defect, other than transport mediated by STRA6 receptor, might have an etiological role in the development of this multiple congenital anomalies syndrome.

Acrochordons are frequently encountered benign skin lesions that may occasionally represent underlying pathology. Pancreatic islet-cell tumors are rare neoplasms and few cases have been described in patients with tuberous sclerosis complex (TSC). A 39-year-old man presenting in acute renal failure was referred to us for further diagnostic evaluation of coincidentally noted dysmorphic features. Physical examination revealed over 1,000 acrochordons in addition to findings meeting criteria for TSC. The diagnosis was confirmed by disclosure of mutation in the TSC2 gene. Further evaluation revealed pancreatic islet cell tumors. Acrochordons are a common skin lesion, but when presenting in an atypical manner or unusual number may be a sign of TSC and underlying occult pathology thereby warranting evaluation of TSC2. Additionally, mutations in TSC2 gene may be a risk factor for developing pancreatic islet-cell tumors., (Copyright 2006 Wiley-Liss, Inc.)

Mayer-Rokitansky-Küster-Hauser (MRKHA) is a malformation complex comprising absent vagina and absent or rudimentary uterus. The aim of our study was to describe the type and frequency of anomalies associated with the MRKHA. Between 1975 and 2002, 25 patients with a diagnosis of MRKHA were identified at the Mayo Clinic. These charts were reviewed retrospectively. Two of the 25 patients were found to have absence of one ovary and two patients had unilateral oophorectomies performed for benign cysts. Four patients had minor anomalies and two had digital anomalies. The frequency of scoliosis (20%), unilateral renal agenesis (28%), non-vertebral skeletal anomalies (16%) and of the MURCS association (Mullerian agenesis, renal agenesis/ectopia and cervical somite dysgenesis), 16%, was similar compared to that of other published studies. Vertebral abnormalities were found more frequently in our patients (44%). Four patients had cardiac defects, an anomaly not previously described, including truncus arteriosus, patent ductus arteriosus and patent foramen ovale, mitral valve prolapse, and mild mitral regurgitation. We document cardiac anomalies in 16% of our patients with MRKHA suggesting that a search for associated anomalies including cardiac defects is indicated in all such patients.

The use of subtelomeric FISH probes has greatly supplemented conventional chromosome analysis in detecting cryptic anomalies in patients with mental retardation (MR), dysmorphic features, and congenital malformations. We report a 3-month-old boy who was diagnosed with ambiguous genitalia, dysmorphic features, and developmental delay. Standard chromosome studies on blood revealed a chimeric karyotype of 46,XY,t(4;5)(q31.1;q14)[46]/46,XX[4]. The boy had intra-abdominal gonads that were testicular in origin by biopsy. Multiple dysmorphic features, marked hypotonia, developmental delay, poor growth, and relative macrocephaly were noted on physical exam. His 2.5-year-old sister also presented with hypotonia, developmental delay, relative macrocephaly, and similar dysmorphic stigmata. In addition, she was diagnosed with several internal malformations. Her karyotype was 46,XX. Due to the striking phenotypic similarity, subtelomeric FISH studies were initiated in the siblings. In addition to the known balanced karyotypic abnormalities, the boy was found to have a derivative chromosome 5 with a 5pter deletion and a 17pter duplication. This cryptic abnormality was also detected in his sister. Chromosome analysis of the father revealed a subtle balanced t(5;17)(p15.31;p13.1) which was confirmed by subtelomeric FISH, whereas the mother's chromosome complement was normal. This familial constellation illustrates the usefulness of subtelomeric FISH in the diagnosis of cryptic chromosome abnormalities in patients for whom conventional karyotype does not disclose findings sufficient to explain the observed phenotypic anomalies., (Copyright 2003 Wiley-Liss, Inc.)

Chromosome anomalies are responsible for a significant proportion of patients with mental retardation, and congenital anomalies. Development of new molecular cytogenetic techniques has provided a powerful tool for detection of patients with subtle chromosome abnormalities. Particularly, investigation of the gene-rich subtelomeric regions has generated interest regarding the implications and prevalence of cryptic chromosomal rearrangements. Here we describe an adult with a submicroscopic deletion of 18pter, detected by subtelomeric FISH probe. The patient is a 42-year-old man with a history of developmental delay, moderate mental retardation, and symptoms of paranoid schizophrenia since adolescence. His physical examination is remarkable for only a few dysmorphic findings typically seen in 18p- syndrome (round face, hypertelorism, down-slanted palpebral fissures, temporal narrowing, small hands and feet). He lacks significant short stature, skin changes, and associated anomalies involving internal organs. All known patients with deletions of the short arm of chromosome 18 have either loss of large parts of 18p or of the entire p-arm, or have complex chromosomal rearrangement involving other chromosomes. To our knowledge, this is the first description of a cryptic subtelomeric deletion of 18p and the first case of such a chromosomal anomaly in a patient with schizophrenia. Small subtelomeric chromosomal deletions would be missed by standard G-banded karyotyping. Therefore, FISH analysis using subtelomeric probes should be considered for diagnostic evaluation of patients with psychiatric symptoms and mental retardation in whom the karyotype is normal., (Copyright 2003 Wiley-Liss, Inc.)