Dataset Information

MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.

ABSTRACT: Investigation of disorders of sex development (DSD) has resulted in the discovery of multiple sex-determining genes. MAP3K1 encodes a signal transduction regulator in the sex determination pathway and is emerging as one of the more common genes responsible for 46,XY DSD presenting as complete or partial gonadal dysgenesis. Clinical assessment, endocrine evaluation, and genetic analysis were performed in six individuals from four unrelated families with 46,XY DSD. All six individuals were found to have likely pathogenic MAP3K1 variants. Three of these individuals presented with complete gonadal dysgenesis, characterized by bilateral streak gonads with typical internal and external female genitalia, while the other three presented with partial gonadal dysgenesis, characterized by incomplete testicular development, resulting in clitoral hypertrophy with otherwise typical female external genitalia. Testing for MAP3K1 variants should be considered in patients with 46,XY complete or partial gonadal dysgenesis, particularly in families with multiple members affected with 46,XY DSD. Identification of a MAP3K1 variant should prompt an evaluation for DSD in female siblings of the proband.

SUBMITTER: Granados A

PROVIDER: S-EPMC5489227 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.

Granados Andrea A Alaniz Veronica I VI Mohnach Lauren L Barseghyan Hayk H Vilain Eric E Ostrer Harry H Quint Elisabeth H EH Chen Ming M Keegan Catherine E CE

American journal of medical genetics. Part C, Seminars in medical genetics 20170515 2

Investigation of disorders of sex development (DSD) has resulted in the discovery of multiple sex-determining genes. MAP3K1 encodes a signal transduction regulator in the sex determination pathway and is emerging as one of the more common genes responsible for 46,XY DSD presenting as complete or partial gonadal dysgenesis. Clinical assessment, endocrine evaluation, and genetic analysis were performed in six individuals from four unrelated families with 46,XY DSD. All six individuals were found t ...[more]

PMID: 28504475

Similar Datasets

Project description:Purpose: Patients with syndromic 46, XY disorders/differences of sex development (DSD) are characterized by gonadal and phenotypic genders inconsistent with their chromosomal sexes as well as abnormalities of multiple extragonadal organs. They are caused by mutations in specific genes, which are expressed in the affected organs and regulate their development, and over fourteen genes have been identified. In this study, we aimed to determine the underlying cause of a patient with syndromic 46, XY DSD and review the clinical presentations and genetic findings of all reported similar cases. Methods: Whole-exome sequencing (WES) was performed to find a molecular cause of the patient. In silico tools were used to analyze the pathogenicity of the variants. Reports of cases with similar clinical features and involved genes were summarized by searching through PubMed/MEDLINE using keywords "PPP2R3C" or "G5PR" and "46,XY disorders of sex development". Results: Compound heterozygous variants (p.F229del/p.G417E) in PPP2R3C were identified in the 24-year-old female by WES and verified by Sanger sequencing. The patient presents complete testicular dysgenesis, low birth weight, facial deformity, cubitus valgus, and decreasing number of CD19+ B lymphocytes and CD4+ T lymphocytes. A total of thirteen 46, XY DSD cases with four homozygous PPP2R3C mutations (p.Leu103Pro, p.Leu193Ser, p.Phe350Ser, and p.Ser216_Tyr218dup) have been reported previously, and their clinical manifestations are roughly similar to those of our patient. Conclusion: Novel compound heterozygous variants in PPP2R3C cause specific syndromic 46, XY gonadal dysgenesis, which broadened the pathogenic variants spectrum of PPP2R3C. The typical phenotype of PPP2R3C mutation is complete 46, XY gonadal dysgenesis with multiple extragonadal anomalies, including facial deformities, skeletal system abnormalities, muscle abnormalities, impaired nervous system, impaired hearing and vision, heart and kidney anomalies, and gastrointestinal dysfunction.

Project description:BACKGROUND:Cutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far either: (I) as an purely cutaneous trait; (II) as a part of a complex malformation phenotype (Ruggieri-Happle syndrome, RHS) including distinct facial features, eye (cataract), skeletal (skull and vertebral defects, and long bones dysplasia), nervous system (corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly) and systemic abnormalities; (III) as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata); and (IV) in association with other skin disturbances [e.g., cutis marmorata telangectasica congenita (phacomatosis achromico-melano-marmorata)] or in the context of other skin (e.g., ataxia-telangiectasia and phacomatosis pigmentovascularis, PPV) or complex malformation phenotypes (e.g., microcephaly and dwarfism). METHODS:(I) Review of the existing literature; and (II) information on our personal experience (clinical, laboratory and imaging data) on new cases with cutis tricolor seen and followed-up at our institutions during years 2010-2016. RESULTS:The existing literature revealed 19 previous studies (35 cases) with pure cutaneous or syndromic cutis tricolor phenomena. Our personal experience included 5 unpublished patients (3 boys; 2 girls; currently aged 2 to 14 years) seen and followed-up at our Institutions in Italy who had: (I) skin manifestations of the cutis tricolor type (N=5); (II) skeletal abnormalities including small skull (n=2), obtuse angle of mandible (n=3), mild to moderate scoliosis (n=3), vertebral defects (n=3), and long bones bowing (n=3); mild psychomotor delay (n=3); epilepsy (n=2); anomalies of the corpus callosum (n=3); and cavum vergae (n =2). CONCLUSIONS:This study further confirms and expands the overall phenotype of cutis tricolor. By literature review and personal experience we conclude that the skin abnormalities of the cutis tricolor type are stable over time; the skeletal defects are mild to moderate and do not progress or cause relevant orthopaedic complications; the neurological/behavioural phenotype does not progress and the paroxysmal events (when present) tend to decrease over time; there is a typical facial phenotype in some patients (long, elongated face, thick and brushy eyebrows, hypertelorism, deep nasal bridge with large bulbous nose and anteverted nostrils), which characterizes a somewhat distinct syndromic phenotype; some patients may develop early onset cataracts. The allelic dydymotic hypothesis of post-zygotic mutations likely involving the same gene loci could well explain the overall skin, bone, lens and nervous system phenomena of migration of different streaks of clones in the different tissues.

Dataset Information

MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.

Publications

MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets