TaoMedAI/RareMedData huggingface dataset:
3-hydroxyisobutyric aciduria (ORPHA:939)
A rare classic organic aciduria characterized by tissue accumulation and elevation of urinary excretion of 3-hydroxyisobutyric acid. The clinical phenotype ranges from recurrent mild episodes of vomiting with normal cognitive development, to massive acidosis, seizures, and failure to thrive with profound intellectual disability and early death. Dysmorphic craniofacial features (such as microcephaly, triangular face, short, sloping forehead, long, prominent philtrum, and micrognathia) and variable cerebral anomalies have also been described.
3-methylglutaconic aciduria type 1 (ORPHA:67046)
3-methylglutaconic aciduria (3-MGA) type I is an inborn error of leucine metabolism with a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia.
Epidemiology
The disorder is very rare with less than 20 cases reported in the literature.
Clinical description
Clinical manifestations usually become apparent in the neonatal period or during infancy but the diagnosis may not be made until childhood. Some of the reported patients also displayed hypoglycaemia, spastic quadriparesis, microcephaly, progressive neurological deficit, seizures, vomiting, atrophy of the basal ganglia, severe hypotonia and hepatomegly.
Etiology
The syndrome is caused by mutations in the AUH gene (chromosome 9) encoding 3-methylglutaconyl-CoA hydratase, an enzyme involved in leucine degradation.
Diagnostic methods
As the clinical picture is variable and nonspecific, diagnosis can be made by assay of 3-methylglutaconyl-CoA hydratase activity in fibroblasts or leukocytes, quantitative analysis of urinary organic acid excretion or, more recently, analysis of bodily fluids by NMR spectroscopy.
Differential diagnosis
Patients with 3-MGA type I can be distinguished from those with other forms of 3-MGA (types II, III and IV; see these terms) by the distinctive pattern of metabolite excretion: 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA) whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA).
Antenatal diagnosis
Prenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes.
Genetic counseling
The syndrome is inherited as an autosomal recessive trait.
Management and treatment
Treatment is largely symptomatic but dietary management with a modest leucine restriction and supplementation with L-carnitine may be beneficial in some cases.

                            Last update: 
                            March 2007


                            - Expert reviewer(s): 
                            Pr Pascale DE LONLAY
3-methylglutaconic aciduria type 3 (ORPHA:67047)
3-methylglutaconic aciduria type III (MGA III) is an organic aciduria characterised by the association of optic atrophy and choreoathetosis with 3-methylglutaconic aciduria.
Epidemiology
The vast majority of reported cases involved the Iraqi-Jewish population, in which the prevalence of the disorder has been estimated at around 1 in 10 000.
Clinical description
Onset of the optic atrophy occurs during infancy with a progressive decrease in visual acuity. The choreoathetoid movement disorder manifests later, usually within the first ten years of life. Other clinical features may include spastic paraparesis, mild ataxia and cognitive deficit, dysarthria, and nystagmus.
Etiology
MGA III is caused by mutations in the OPA3 gene (19q13.2-q13.3). The biological function of the OPA3 gene product remains to be defined but MGA III is hypothesised to be a primary mitochondrial disorder.
Diagnostic methods
Diagnosis may be suspected up on presentation with early-onset optic atrophy and choreoathetosis (particularly in individuals of Iraqi-Jewish origin) and by detection of an elevation in the levels of 3-methylglutaconic and 3-methylglutaric acid in the urine. Diagnosis can be confirmed by detection of mutations in the OPA3 gene.
Differential diagnosis
MGA type III can be distinguished from other forms of MGA (types I, II and IV; see these terms) on the basis of the clinical phenotype and, more specifically, from 3-MGA type I by the absence of an elevation in 3-hydroxyisovaleric acid levels and normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. The differential diagnosis may also include Behr syndrome (see this term) and cerebral palsy.
Antenatal diagnosis
Prenatal testing is clinically available for affected families through molecular analysis of amniocytes or chorionic villus samples.
Genetic counseling
MGA III is transmitted as an autosomal recessive trait.
Management and treatment
Treatment is symptomatic only and should be managed by a multidisciplinary team.
Prognosis
The long-term prognosis remains unknown: although the disease progresses during childhood, it appears to stabilise during early adulthood.

                            Last update: 
                            March 2007


                            - Expert reviewer(s): 
                            Pr Pascale DE LONLAY
3-methylglutaconic aciduria type 4 (ORPHA:67048)
3-methylglutaconic aciduria (3-MGA) type IV, or unclassified 3-MGA, is a clinically heterogeneous disorder characterised by increased 3-methylglutaconic acid excretion in individuals that cannot be classified as having one of the other forms of 3-MGA (3-MGA I, II or III).
Epidemiology
The prevalence of this disorder is unknown.
Clinical description
Patients usually present during the first year of life with neurological findings including psychomotor retardation, hypotonia, developmental delay, seizures and progressive spasticity, together with severe failure to thrive. Cardiomyopathy, hepatic dysfunction, eye anomalies, microcephaly, deafness, dysmorphism, neonatal hypoglycaemia, thrombocytopaenia and lactic acidosis have also been reported. Cerebellar dysgenesis may be revealed by magnetic resonance imaging. In contrast, a small number of asymptomatic patients have been diagnosed as having 3-MGA type IV.
Etiology
The aetiology remains unknown: unlike patients with 3-MGA type I, individuals with 3MGA type IV display normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. Mitochondrial respiratory chain abnormalities have been detected in some 3MGA type IV patients but the clinical heterogeneity associated with this disorder suggests that the 3-methylglutaconic aciduria seen in 3-MGA type IV patients may result from a variety of causes and genetic factors.
Diagnostic methods
3-methylglutaconic aciduria can be diagnosed by analysis of urinary organic acid excretion but specific diagnosis of 3-MGA type IV requires exclusion of all other forms of 3-MGA. As the genetic factors responsible for the other forms of 3-MGA have now been determined, molecular analysis provides a valuable tool for accurate diagnosis.
Differential diagnosis
3-MGA type IV can be distinguished from the type I disorder by normal excretion of 3-hydroxyisovaleric acid. 3-MGA type II may be excluded by the mode of inheritance (transmission is X-linked recessive in 3-MGA type II) and on the basis of the clinical phenotype (the type II disorder is characterised by neutropaenia, skeletal myopathy, dilated cardiomyopathy and growth delay). Depending on the manifestations present, clinical differentiation of types III and IV may be more problematic, but the occurrence of 3-MGA type III is largely restricted to the Iraqi-Jewish population. In addition to other forms of 3-MGA, the differential diagnosis should also include cerebral palsy, dilated cardiomyopathy with ataxia (see this term) and other organic acidurias.
Genetic counseling
The disorder has been reported to be inherited as an autosomal recessive trait.
Management and treatment
At present there is no effective treatment for 3-MGA type IV and a leucine-restricted diet appears to be of no benefit.
Prognosis
The prognosis depends on the clinical phenotype but the neurological complications can be severe with a potentially fatal disease course.

                            Last update: 
                            March 2007


                            - Expert reviewer(s): 
                            Pr Pascale DE LONLAY
3-methylglutaconic aciduria type 8 (ORPHA:505208)
A rare organic aciduria characterized by neonatal onset of hypotonia, recurrent apneic episodes, lack of psychomotor development, feeding difficulties, extrapyramidal signs, and seizures. Other reported features include microcephaly, sensorineural deafness, bradycardia, and neutropenia. Laboratory studies show increased serum lactate and urinary excretion of 3-methylglutaconic acid. Brain imaging may reveal progressive cerebral atrophy. The disease is lethal in infancy.
3-methylglutaconic aciduria type 9 (ORPHA:505216)
A rare organic aciduria characterized by early onset of global developmental delay with severe intellectual disability, seizures, and 3-methylglutaconic aciduria. Additional features are hypotonia, hyperactivity and aggressive behavior, optic atrophy, or spasticity. Brain imaging may show generalized cerebral atrophy and white matter abnormalities.
3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome (ORPHA:445038)
A rare organic aciduria characterized by increased urinary excretion of 3-methylglutaconic acid, variably associated with neutropenia (sometimes causing recurrent severe infections and potentially resulting in leukemia) and progressive neurologic manifestations, such as global developmental delay, intellectual disability, hypotonia, movement disorder, and seizures. Microcephaly, cataract, facial dysmorphism, growth retardation, endocrine abnormalities, and cardiomyopathy have also been reported. Brain imaging may show cerebral or cerebellar atrophy, or abnormalities of the basal ganglia.
3-phosphoglycerate dehydrogenase deficiency, infantile/juvenile form (ORPHA:79351)
3-Phosphoglycerate dehydrogenase deficiency (3-PGDH deficiency) is an autosomal recessive form of serine deficiency syndrome (see this term) characterized clinically in the few reported cases by congenital microcephaly, psychomotor retardation and intractable seizures in the infantile form and by absence seizures, moderate developmental delay and behavioral disorders in the juvenile form
3-phosphoserine phosphatase deficiency, infantile/juvenile form (ORPHA:79350)
3-Phosphoserine phosphatase deficiency is an extremely rare form of serine deficiency syndrome (see this term) characterized clinically by congenital microcephaly and severe psychomotor retardation in the single reported case to date, which was associated with Williams syndrome (see this term).
3MC syndrome (ORPHA:293843)
A rare multiple congenital anomalies syndrome characterized by a spectrum of developmental anomalies including cleft lip and/or palate, craniosynostosis, intellectual disability and/or learning disability, radioulnar synostosis, genital and vesicorenal anomalies. Observed facial dysmorphism includes hypertelorism, blepharophimosis, blepharoptosis, high arched eyebrows. Less common features reported include anterior chamber defects, cardiac anomalies (e.g. ventricular septal defect; see this term), caudal appendage, umbilical hernia/omphalocele and diastasis recti.
Epidemiology
Prevalence data is limited. To date less than 35 cases have been reported in the literature worldwide.
Clinical description
Diagnosis is often made at birth, in newborns presenting with craniosysnostosis, cleft lip and/or palate and typical facial dysmorphism. Diagnosis could be made antenatally if the fetus presents omphalocele, facial cleft, caudal appendage or sacral anomalies. Children have psychomotor and growth delay. Intellectual disability forms part of the spectrum, and when present is typically moderate; however, patients are sometimes only limited by learning difficulties. Hearing loss is possible and should be monitored. Radioulnar synostosis, vesicorenal and genital anomalies can also occur.
Etiology
3MC syndrome is due to biallelic point mutations or deletions in one of the 3 known causative genes COLEC10 (8q24.12), COLEC11 (2p25.3), and MASP1 (3q27.3). These genes code for factors involved in the activation of complement via the lectin or alternative pathways.
Diagnostic methods
Diagnosis is suspected on clinical presentation (particularly by the association of craniosynostosis, intellectual disability and typical facial dysmorphism) and confirmed by genetic testing including targeted sequencing of the 3 genes COLEC10, COLEC11 and MASP1/3.
Differential diagnosis
Differential diagnosis includes syndromic craniosynostoses, such as Crouzon disease.
Antenatal diagnosis
Prenatal diagnosis is possible if a pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Consanguineous families are more prone to present this rare disorder.
Management and treatment
Early surgical repair is provided for craniosynostosis, cleft lip/palate, caudal appendage.
Prognosis
Prognosis is linked to visceral malformations, growth restriction and intellectual disability.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Pr Caroline ROORYCK-THAMBO | ITHACA*


                                * European Reference Network
3p25.3 microdeletion syndrome (ORPHA:435638)
3p25.3 microdeletion syndrome is a rare chromosomal anomaly characterized by intellectual disability, epilepsy or EEG abnormalities, poor speech, ataxia, and stereotypic hand movements.
3q13 microdeletion syndrome (ORPHA:1621)
3q13 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from a partial deletion of the long arm of chromosome 3. Phenotype can be highly variable, but it is primarily characterized by significant developmental delay, postnatal growth above the mean, muscular hypotonia and distinctive facial features (such as broad and prominent forehead, hypertelorism, epicantic folds, anti-mongloid slanted eyes, ptosis, short philtrum, protruding lips with a full lower lip, high arched palate). Abnormal hypoplastic male genitalia and skeletal abnormalities are frequently present.
3q26 microduplication syndrome (ORPHA:96095)
A rare chromosomal anomaly characterized by prenatal and postnatal growth retardation, developmental delay, intellectual impairment, dysmorphic signs and variable combination of congenital anomalies, including cardiovascular, genitourinary and skeletal anomalies and spectrum of caudal malformations.
3q26q27 microdeletion syndrome (ORPHA:356947)
A rare partial autosomal microdeletion syndrome characterized by neonatal hypotonia, prenatal and postnatal growth deficiency, severe feeding difficulties, global developmental delay and intellectual disability, dental anomalies (delayed tooth eruption, delayed loss of primary teeth, dental crowding), recurrent respiratory infections, thrombocytopenia and facial dysmorphism (flat facial profile, medially sparse eyebrows, epicanthal folds, flat nasal bridge and tip, short philtrum). Behavioral abnormalities (ADHD, Asperger syndrome) have also been reported.
3q27.3 microdeletion syndrome (ORPHA:397695)
3q27.3 microdeletion syndrome is a rare chromosomal anomaly syndrome, resulting from the partial deletion of the long arm of chromosome 3, characterized by mild to severe intellectual disability, neuropsychiatric disorders of the psychotic and dysthymic spectrum, mild distinctive facial dysmorphism (incl. slender face, deep-set eyes, high nasal bridge with a hooked nose, small, low- set ears, short philtrum, small mouth with thin upper lip, prognathism) and a marfanoid habitus.
3q29 microdeletion syndrome (ORPHA:65286)
A recurrent subtelomeric deletion syndrome with variable clinical manifestations including intellectual deficit and dysmorphic features.
Epidemiology
It has been described in 23 patients.
Clinical description
The clinical phenotype is extremely variable. The most common features include mild-to-moderate intellectual deficit and slightly dysmorphic facial features: microcephaly, long and narrow face, short philtrum, large posteriorly rotated ears and high nasal bridge. Autism and gait ataxia have been noted occasionally. Congenital malformations are not common: there are only rare reports of horseshoe kidney, hypospadias and congenital heart defects (patent ductus arteriosus).
Etiology
The syndrome is caused by a recurrent deletion of the 3q subtelomeric region. The microdeletion is commonly 1.6 Mb in length and encompasses more than 20 genes. It was identified by comparative genomic hybridization (CGH) microarray or fluorescence in situ hybridization (FISH) and the underlying mechanism is likely non-allelic homologous recombination (NAHR). Most of the deletions appear de novo  but a few of them were inherited from mildly or non-affected parents. More recently an infant and his father, both with 3q29 microdeletion and cardiac defects, were described as intellectually normal.

                            Last update: 
                            January 2011


                            - Expert reviewer(s): 
                            Dr Nicole MORICHON-DELVALLEZ
3q29 microduplication syndrome (ORPHA:251038)
3q29 microduplications are recently described chromosomal abnormalities with unclear clinical significance.
Epidemiology
They have been reported in fewer than 30 patients.
Clinical description
The clinical phenotype is extremely variable and the most consistent features are mild or moderate intellectual deficit and microcephaly.
Etiology
Among duplications, only some appear to be the reciprocal duplication products of 3q29 microdeletion (see this term) and the others flank, span, or partially overlap the common deletion region. These results suggest that other mechanisms in addition to non-allelic homologous recombination (NAHR) mediate rearrangements of 3q29. These microduplications appear de novo or are inherited from mildly affected or completely normal parents. The clinical significance of reciprocal 3q29 microduplication is still unclear.

                            Last update: 
                            March 2011


                            - Expert reviewer(s): 
                            Dr Nicole MORICHON-DELVALLEZ
46,XX difference of sex development-anorectal anomalies syndrome (ORPHA:2973)
A rare developmental defect during embryogenesis characterized by a normal female karyotype, normal ovaries, male or ambiguous genitalia, urinary tract malformations (ranging from bilateral renal agenesis to mild unilateral hydronephrosis), Müllerian duct anomalies (e.g. complete absence of the uterus and vagina, bicornuate uterus), and imperforate anus. Additional features may include tracheoesophageal fistula, radial aplasia, and malrotation of the gut.
46,XX difference of sex development-skeletal anomalies syndrome (ORPHA:2975)
A rare difference of sex development characterized by primary amenorrhea and ambiguous external genitalia (enlarged clitoris with marked fusion of the labioscrotal folds) in association with skeletal anomalies (such as hypoplasia of the mandibular condyles and the maxilla, and ulnar dislocation of the radial heads), in the presence of a 46,XX karyotype and regular ovaries, fallopian tubes, and uterus. There have been no further descriptions in the literature since 1972.
46,XX gonadal dysgenesis (ORPHA:243)
A rare disorder/difference of sex development characterized by a primary ovarian defect, either a failure of the gonads to develop or resistance to gonadotrophin stimulation which leads to premature ovarian failure (POF) in otherwise phenotypically female 46,XX individuals.
Epidemiology
Prevalence is unknown.
Clinical description
Patients are born with typical female sex characteristics without ambiguity. However, affected individuals present during adolescence or young adulthood with either delayed or absent puberty resulting in primary or sometimes secondary amenorrhea. The internal and external genitalia are typically developed. 46,XX gonadal dysgenesis can occur as part of Perrault syndrome (ovarian dysgenesis and deafness with or without cerebellar ataxia), as well as other rare syndromes such as lung fibrosis-immunodeficiency-gonadal dysgenesis.
Etiology
Ovarian dysgenesis results from genetic defects of ovarian development. Although the underlying etiology remains unknown in most cases, several genes have been implicated including homozygous or compound heterozygous inactivating mutations of the follicle-stimulating hormone receptor gene (FSHR; 2p21-p16), mutations in the BMP15 gene (Xp11.2) and mutations in the NR5A1 gene (9q33), amongst others.
Diagnostic methods
Diagnosis requires an evaluation of hormonal status (gonadal and adrenal), laboratory investigations to screen for infectious or autoimmune disorders, karyotype analysis, molecular studies and sometimes laparoscopy with biopsy of ovarian tissue.
Differential diagnosis
The differential diagnosis should include other causes of POF, as well as 46,XY complete gonadal dysgenesis. In addition, secondary ovarian hypoplasia has been described in association with infectious agents (HIV) or autoimmunity (APECED syndrome associated with AIRE gene mutations).
Antenatal diagnosis
Prenatal molecular diagnosis is feasible in cases where a mutation has been identified in the family.
Genetic counseling
Genetic counseling may be offered. Inactivating FSHR mutations are inherited in an autosomal recessive manner, BMP15 mutations are inherited in an X-linked manner and NR5A1 mutations are autosomal dominant in the great majority of cases.
Management and treatment
Management should include hormone replacement therapy. Calcium and vitamin D supplements may also be proposed. Psychological support should also be offered to patients and their families in a difference/disorder of sexual development-center setting. Infertility is an important management issue; however, pregnancy may be feasible through zygote egg donation.
Prognosis
With appropriate management, the physiological and clinical outcome for patients is good.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Pr Olaf HIORT | Endo-ERN*


                                * European Reference Network
46,XX ovarian dysgenesis-short stature syndrome (ORPHA:444048)
A rare genetic disorder with difference of sex development characterized by primary amenorrhea, short stature, delayed bone age, decreased levels of estradiol, elevated levels of follicle-stimulating hormone and luteinizing hormone, absent or underdeveloped uterus and ovaries, delayed development of pubic and axillary hair, and normal 46,XX karyotype.
46,XY difference of sex development due to isolated 17,20-lyase deficiency (ORPHA:90796)
A rare difference of sex development due to reduced 17,20-lyase activity that affects individuals with 46,XY karyotype and is characterized by female or atypical external genitalia with reduced phallic size, hypospadias, incomplete fusion of the labioscrotal swellings, cryptorchidism, and a blind vaginal pouch. Blood pressure and electrolytes are normal whilst hormonal investigations show normal basal and stimulated levels of cortisol, and low basal and stimulated androgen levels.