ABSTRACT
The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
Subject(s)
Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genomics/methods , Cystic Fibrosis/diagnosis , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Genotype , Humans , Mutation/genetics , PhenotypeABSTRACT
MBTPS1 (NM_003791.4) encodes Site-1 protease, a serine protease that functions sequentially with Site-2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo-Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, and Silver-Russell-like syndrome). In this report, we describe a 14-year-old female with a complex medical history including white matter volume loss, early-onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA-seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non-sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1-related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene-related disorders.
Subject(s)
Ectodermal Dysplasia , Genetic Testing , Adolescent , Female , Humans , Ectodermal Dysplasia/diagnosis , Ectodermal Dysplasia/genetics , Genotype , Mutation , Phenotype , SyndromeABSTRACT
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.
Subject(s)
Genetics, Medical , Humans , History, 20th Century , History, 21st Century , Human GeneticsABSTRACT
PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.
Subject(s)
Achondroplasia , Child , Male , Female , Humans , Child, Preschool , Prospective Studies , Achondroplasia/epidemiology , Achondroplasia/genetics , Achondroplasia/diagnosis , Body HeightABSTRACT
We report on a 26-year-old male with extreme short stature, microcephaly, macroglossia, other dysmorphic features, severe intellectual disability, and a bone dysplasia. The patient had an extensive genetic and biochemical evaluation that was all normal or noninformative. Recently, the proband died following a period of not eating. He likely had a previously undescribed syndrome of unknown etiology.
Subject(s)
Abnormalities, Multiple/etiology , Bone Diseases, Developmental/etiology , Dwarfism/etiology , Adult , Bone Diseases, Developmental/diagnostic imaging , Face/abnormalities , Female , Fetal Growth Retardation , Humans , Infant, Newborn , Intellectual Disability , Male , Microcephaly/etiology , Pregnancy , SyndromeABSTRACT
EVEN-PLUS syndrome is a rare condition characterized by its involvement of the Epiphyses, Vertebrae, Ears, and Nose, PLUS other associated findings. We report here the fifth case of EVEN-PLUS syndrome with novel variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in the HSPA9 gene identified through whole-exome sequencing. The patient is the first male known to be affected and presented with additional features not previously described with EVEN-PLUS syndrome. These features include agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. qPCR analysis provides supporting evidence for a nonsense-mediated decay mechanism for the HSPA9 truncating variant. In silico 3D modeling supports the pathogenicity of the c.955C > T (p.L319F) missense variant. The study presented here further describes the syndrome and broadens its mutational and phenotypic spectrum. Our study also lends support to HSPA9 variants as the underlying etiology of EVEN-PLUS syndrome and ultimately provides a better understanding of the molecular basis of the condition.
Subject(s)
HSP70 Heat-Shock Proteins/genetics , Mitochondrial Proteins/genetics , Musculoskeletal Abnormalities/genetics , Mutation, Missense , Septum Pellucidum/pathology , Clubfoot/complications , Cryptorchidism/complications , Exome , Genetic Association Studies , Genetic Variation , Humans , Hydronephrosis/complications , Imaging, Three-Dimensional , Infant , Karyotyping , Male , Muscle Hypotonia/complications , Mutation , Phenotype , RNA, Messenger/metabolism , Ribs/abnormalities , Septum Pellucidum/abnormalities , Sternum/abnormalities , Syndrome , Exome SequencingABSTRACT
The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss-of-function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2-associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED-associated overgrowth (Cohen-Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.
Subject(s)
Enhancer of Zeste Homolog 2 Protein/genetics , Growth Disorders/genetics , Phenotype , Polycomb Repressive Complex 2/genetics , Humans , Neoplasm Proteins , Syndrome , Transcription FactorsABSTRACT
Wiedemann-Steiner syndrome is a genetic condition associated with dysmorphic facies, hypertrichosis, short stature, developmental delay, and intellectual disability. Congenital malformations of the cerebral, cardiac, renal, and optic structures have also been reported. Because the majority of reported individuals with this condition have been under age 20, the long-term prognosis is not well defined. Here we report on two further unrelated individuals diagnosed with Wiedemann-Steiner syndrome, one of whom is in her third decade of life. In addition, both individuals have novel KMT2A mutations. The information provided below about the outcome in Wiedemann-Steiner syndrome is important for families of affected individuals.
Subject(s)
Abnormalities, Multiple/genetics , Contracture/genetics , Developmental Disabilities/genetics , Growth Disorders/genetics , Histone-Lysine N-Methyltransferase/genetics , Hypertrichosis/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Child , Child, Preschool , Contracture/physiopathology , Developmental Disabilities/physiopathology , Disease Progression , Facies , Female , Growth Disorders/physiopathology , Humans , Hypertrichosis/physiopathology , Infant , Intellectual Disability/physiopathology , Male , Microcephaly/physiopathology , Musculoskeletal Abnormalities/genetics , Musculoskeletal Abnormalities/physiopathology , Phenotype , Young AdultABSTRACT
Coffin-Lowry syndrome (CLS) is a rare X-linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high-resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT-PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss-of-function mechanism. PCR analysis of the patients' cDNA detected a band greater than expected for an exon 4-10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next-generation sequencing and high-resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases.
Subject(s)
Chromosome Duplication , Coffin-Lowry Syndrome/diagnosis , Coffin-Lowry Syndrome/genetics , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Siblings , Child , Facies , Genetic Association Studies , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Male , Mutation , Pedigree , PhenotypeABSTRACT
The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.
Subject(s)
Alopecia/genetics , Mandibulofacial Dysostosis/genetics , Receptor, Endothelin A/genetics , Alopecia/pathology , Animals , Base Sequence , Endothelin-1/metabolism , Exome/genetics , Humans , In Situ Hybridization , Mandibulofacial Dysostosis/pathology , Molecular Sequence Data , Morpholinos/genetics , Mutation, Missense/genetics , Pedigree , RNA, Messenger/administration & dosage , Real-Time Polymerase Chain Reaction , Receptor, Endothelin A/metabolism , Sequence Analysis, DNA , Syndrome , Tomography, X-Ray Computed , Zebrafish , Zygoma/pathologyABSTRACT
Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.
Subject(s)
Abnormalities, Multiple/genetics , Arachnodactyly/genetics , Arthrogryposis/genetics , Blepharophimosis/genetics , Cleft Palate/genetics , Clubfoot/genetics , Connective Tissue Diseases/genetics , Contracture/genetics , Hand Deformities, Congenital/genetics , Ion Channels/genetics , Ophthalmoplegia/genetics , Retinal Diseases/genetics , Abnormalities, Multiple/pathology , Arachnodactyly/pathology , Arthrogryposis/pathology , Blepharophimosis/pathology , Child , Child, Preschool , Cleft Palate/pathology , Clubfoot/pathology , Connective Tissue Diseases/pathology , Contracture/pathology , Exome/genetics , Female , Hand Deformities, Congenital/pathology , Humans , Male , Mutation , Ophthalmoplegia/pathology , Pedigree , Retinal Diseases/pathologyABSTRACT
Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.
Subject(s)
Abnormalities, Multiple/enzymology , Abnormalities, Multiple/genetics , Congenital Hypothyroidism/enzymology , Congenital Hypothyroidism/genetics , Craniofacial Abnormalities/enzymology , Craniofacial Abnormalities/genetics , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Hand Deformities, Congenital/enzymology , Hand Deformities, Congenital/genetics , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Female , Histone Methyltransferases , Humans , Infant , Infant, Newborn , Male , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolismABSTRACT
We further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Filamins/genetics , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Mutation , Phenotype , Adolescent , Adult , Child , Exome , Genetic Association Studies , Genetic Linkage , Genotype , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Pedigree , Syndrome , X Chromosome Inactivation , Young AdultABSTRACT
We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.
Subject(s)
Abnormalities, Multiple/genetics , Congenital Hypothyroidism/genetics , Craniofacial Abnormalities/genetics , DNA-Binding Proteins/genetics , Hand Deformities, Congenital/genetics , Mutation , Transcription Factors/genetics , Adolescent , Adult , Base Sequence , Child , Child, Preschool , DNA Mutational Analysis , Enhancer of Zeste Homolog 2 Protein , Exome , Female , Humans , Infant , Male , Molecular Sequence Data , Pedigree , Polycomb Repressive Complex 2 , Young AdultABSTRACT
Setleis syndrome, focal facial dermal dysplasia type III (FFDD3, MIM #227260), is characterized by scar-like bitemporal lesions and other ocular and facial dysmorphic features. The syndrome results from recessive mutations in the TWIST2 gene, encoding a basic helix-loop-helix transcription factor or de novo genomic duplication or triplication, which include 1.3 Mb at 1p36.22p36.21, or other yet undefined lesions, emphasizing the syndrome's genetic heterogeneity. Recently, three patients were reported with 1p36.22p36.21 duplications/triplication that had the characteristic FFDD3 features and developmental delay or intellectual disabilities. Here, we describe a male with this microduplication, and the typical FFDD3 phenotype, but normal intelligence. Notably, his duplication was inherited from his father who did not have any FFDD3 manifestations, indicating lack of penetrance of the 1p36.22p36.21 microduplication. These findings emphasize phenotypic heterogeneity of the 1p36.22p36.21 copy number variant and the importance of screening the parents of patients with the 1p36.22p36.21 copy number variant to determine whether the duplication/triplication is de novo or inherited, for informed reproductive and genetic counseling.
Subject(s)
Chromosome Duplication/genetics , Chromosomes, Human, Pair 1/genetics , Focal Dermal Hypoplasia/genetics , Skin Diseases/genetics , Ectodermal Dysplasia , Female , Focal Dermal Hypoplasia/pathology , Focal Facial Dermal Dysplasias , Humans , Male , Pedigree , Penetrance , Phenotype , Repressor Proteins/genetics , Skin Diseases/pathology , Twist-Related Protein 1/genetics , Young AdultABSTRACT
We report on a 5-month-old female with large and widely spaced anterior and posterior fontanelles, aplasia cutis congenita, Tessier 3 oblique facial cleft, polydactyly, and syndactyly of toes. The polydactyly is unusual as an accessory finger is attached to the left fifth finger with mirrored, end-to-end fusion. We are naming this anomaly "polydactyly inversus." The infant appears to have a previously unreported syndrome of unknown cause.
Subject(s)
Abnormalities, Multiple/diagnostic imaging , Cleft Lip/diagnostic imaging , Cleft Palate/diagnostic imaging , Ectodermal Dysplasia/diagnostic imaging , Polydactyly/diagnostic imaging , Syndactyly/diagnostic imaging , Cranial Fontanelles/abnormalities , Female , Humans , Infant , Radiography , Syndrome , Ultrasonography, PrenatalABSTRACT
Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype.
Subject(s)
Chromosome Duplication , Ectodermal Dysplasia/genetics , Focal Dermal Hypoplasia/genetics , Repressor Proteins/genetics , Skin Diseases/genetics , Twist-Related Protein 1/genetics , Adolescent , Adult , Child, Preschool , Chromosomes, Human, Pair 1/genetics , Ectodermal Dysplasia/physiopathology , Face/pathology , Female , Focal Dermal Hypoplasia/physiopathology , Focal Facial Dermal Dysplasias , Frameshift Mutation , Humans , Infant , Infant, Newborn , Male , Skin Diseases/physiopathologyABSTRACT
In this report, we describe an 8-year-old male with Robin sequence, bilateral radiohumeral synostosis, microgastria, cryptorchidism, dislocated hips, proximal femoral deficiency, and an autism spectrum disorder. This combination of findings has not been previously reported. Features of particular interest are the radiohumeral synostosis and microgastria, both of which are rare defects, and to our knowledge, have not been reported to occur together. We propose that the patient has a newly recognized syndrome consisting of the aforementioned features, the etiology of which is unknown.
Subject(s)
Abnormalities, Multiple/diagnosis , Femur/abnormalities , Hamartoma/diagnosis , Holoprosencephaly/diagnosis , Hypothalamic Diseases/diagnosis , Lung/abnormalities , Microphthalmos/diagnosis , Mullerian Ducts/abnormalities , Pierre Robin Syndrome/diagnosis , Radius/abnormalities , Synostosis/diagnosis , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , Child , Facies , Humans , Male , Phenotype , Radiography , SyndromeABSTRACT
Carpenter syndrome is an autosomal recessive disorder comprising craniosynostosis, polysyndactyly, and brachydactyly. It occurs in approximately 1 birth per million. We present a patient with Carpenter syndrome (confirmed by molecular diagnosis) who has several unique and previously unreported manifestations including a large ovarian cyst and heterotaxy with malrotation of stomach, intestine, and liver. These findings were first noted by prenatal ultrasound and may assist in prenatally diagnosing additional cases of Carpenter syndrome.