Cranio-cerebello-cardiac (3C) syndrome is a rare multiple congenital anomalies syndrome characterized by craniofacial (prominent occiput and forehead, hypertelorism, ocular coloboma, cleft palate), cerebellar (Dandy-Walker malformation, cerebellar vermis hypoplasia) and cardiac (tetralogy of Fallot, atrial and ventricular septal defects) anomalies (see these terms).

Summary:
Epidemiology
To date < 50 cases have been described. The syndrome appears to be panethnic.
Clinical description
3C syndrome is a congenital disorder characterized by distinctive craniofacial features including, in decreasing frequency, low-set ears, hypertelorism, down-slanting palpebral fissures, depressed nasal bridge, prominent occiput, prominent forehead, cleft palate, micrognathia, ocular coloboma. Additional craniofacial features encompass nevus flammeus (on forehead), low posterior hairline, sparse scalp hair, eyebrows and eyelashes, open mouth with protruding tongue, and short neck. In 80% of cases, cerebellar anomalies are present and include primarily Dandy-Walker malformation or Dandy-Walker variant, cerebellar vermis hypoplasia and enlargement of cisterna magma. Affected individuals have gross motor and speech delay and intellectual disability. The cardiovascular anomalies include atrial and ventricular septal defects, patent arterial duct, tetralogy of Fallot, double outlet right ventricle, hypoplastic left heart syndrome (see these terms), aortic or pulmonary stenosis, and other valvular anomalies. Postnatal short stature is noted in most patients, and growth hormone deficiency has been reported in two patients. Additional anomalies, noted in >10% of patients, include feeding difficulties, single umbilical artery, small hands with single transverse crease, camptodactyly, equinovarus deformity, hydronephrosis, shallow scrotum, undescended testis, cryptorchidism, micropenis, hypospadias, nail hypoplasia, hearing loss, malrotation of the gut. Skeletal defects may be present with rib and vertebral anomalies (hemivertebrae). Rarely observed features include ocular (congenital glaucoma, optic nerve atrophy with eyelid ptosis, heteochromatic iris, posterior embryotoxon), renal (multicystic dysplastic kidney, horseshoe kidneys, unilateral renal agenesis) and anal (anal atresia, anteriorly placed anus malformations) anomalies. Single occurrences of renal hypoplasia, nipple hypoplasia, penile hypoplasia, unilateral adrenal aplasia, immunodeficiency have also been reported.
Etiology
The exact etiology is still unknown but mutations in KIAA0196 (8q24.13; coding for strumpellin) have been identified in a First Nations cohort and these mutations may be involved in the pathophysiology of 3C syndrome.
Diagnostic methods
The diagnostic criteria for 3C syndrome include congenital heart malformation(s) other than isolated patent arterial duct; Dandy-Walker malformation, cerebellar vermis hypoplasia, or enlarged cisterna; and cleft palate, ocular coloboma or four of the following: prominent occiput, prominent forehead, hypertelorism, micrognathia, downslanting palpebral fissures, depressed nasal bridge, low-set ears.
Differential diagnosis
Differential diagnosis includes Joubert syndrome, Ellis Van Creveld syndrome, Cornelia de Lange syndrome, distal monosomy 6p (see these terms) and Dandy Walker malformation.
Antenatal diagnosis
Prenatal diagnosis may be suspected after an ultrasound examination revealing characteristic major structural anomalies of 3C syndrome. Prenatal testing is available for families in which the disease-causing mutations have been previously identified.
Genetic counseling
Sporadic and familial cases have been reported. Transmission is autosomal recessive. Phenotypic variability exists between siblings.
Management and treatment
Management is mainly symptomatic and multidisciplinary approaches including educational programs, physical, occupational, and speech therapy may help to improve hypotonia and reduce motor developmental delay. Cardiac malformation requires specific care, often surgery.
Prognosis
Prognosis is determined by the cardiovascular malformation. Motor delay is common and associated with hypotonia secondary to cerebellar anomalies.

                            Last update:
                            September 2015

                            - Expert reviewer(s):
                            Dr Marlène RIO


A rare primordial growth disorder characterized by low birth weight, reduced birth length, severe postnatal growth restriction, large head size, a spectrum of minor anomalies (including facial dysmorphism) and normal intelligence.

Summary:
Epidemiology
Approximately 200 cases have been reported to date and the condition is rare. However, the phenotype is likely under-recognized.
Clinical description
Infants present with severe prenatal and postnatal growth retardation, birth weight usually at or below the 2nd centile. Growth impairment is greater in those with CUL7 variants. The head circumference is relatively large. Characteristic facial features include: triangular-shaped face, pointed chin, frontal bossing, hypoplastic midface, fleshy, upturned nose , prominent mouth and lips. These features often become less noticeable with age. Short broad neck and thorax, prominent trapezii, winged scapulae, square shoulders, hyperlordosis and clinodactyly of the fifth finger are seen in some children. Prominent fleshy heels in infancy are a common and distinctive feature. Joint hypermobility and an increased risk of congenital hip dislocation may be present. Hyperlordosis can cause back pain. Intelligence is unaffected and development is usually normal. Some cases of impaired fertility and hypospadias have been noted in males , though this is not universal, while females have normal ovarian function. Patients reach a final adult height of about 120-130 cm (5-6 standard deviations below the mean).
Etiology
Pathogenic variants in three different genes are known to cause 3M syndrome. Variants in in the CUL7 at 6p21.1 are found in around 75% patients. Other genes known to be involved are OBSL1 (2q35), in 20% of cases and CCDC8 (19q13.33) in 5% of cases. The precise mechanisms leading to growth failure in 3M syndrome remain unclear although the poor response to growth hormone in many patients indicates a degree of resistance to the GH/IGF1 pathway.
Diagnostic methods
Diagnosis is based primarily on clinical features (e.g. low birth weight, severe growth retardation, prominent fleshy heels). In some, specific radiological findings will be found including slender/ 'gracile' long bones, relatively tall vertebral bodies, foreshortening of vertebral bodies with increasing age, small pelvic bones and a broad thorax with slender and horizontal ribs. The occurrence of these radiological findings, however, is highly variable. Children with 3M syndrome usually have normal GH levels. Molecular genetic testing can identify pathogenic variants in one of the causal genes, confirming diagnosis in the majority of cases. Some children with 3M syndrome demonstrate normal-high baseline insulin-like growth factor (IGF-I) concentrations.
Differential diagnosis
Differential diagnoses include Silver-Russell syndrome, Dubowitz syndrome, Mulibrey nanism, fetal alcohol syndrome, and microdeletion of chromosome 20p13p12.
Antenatal diagnosis
Prenatal and preimplantation diagnosis is possible in families with a known disease causing variant.
Genetic counseling
3M syndrome is inherited autosomal recessively and genetic counseling is recommended for affected families. In a family with an index patient, the sibling recurrence risk is 25%.
Management and treatment
Once diagnosed the child should be seen by a pediatric endocrinologist for monitoring of growth and pubertal progress and for consideration of recombinant human growth hormone (GH) therapy. Monitoring of growth every 6-12 months is recommended until achievement of final height. Adaptive aids for people with short stature and physiotherapy are possible treatment options. Newborns should have a hip ultrasound scan to screen for developmental dysplasia of the hip. Children can be treated with recombinant human growth hormone. In general, the response to treatment is relatively poor, however a trial of treatment over 1 year may show a reasonable response. Overall treatment with growth hormone is more successful if started early and continued long term. The issue of fertility should be discussed with male patients at the end of puberty and semen analysis offered.
Prognosis
3M syndrome is not a life-threatening condition and the prognosis is good.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Jill CLAYTON-SMITH | ITHACA*

                                * European Reference Network


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.

Summary:
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 is a rare chromosomal anomaly characterized by intellectual disability, epilepsy or EEG abnormalities, poor speech, ataxia, and stereotypic hand movements.


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.


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.


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 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.


A recurrent subtelomeric deletion syndrome with variable clinical manifestations including intellectual deficit and dysmorphic features.

Summary:
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 microduplications are recently described chromosomal abnormalities with unclear clinical significance.

Summary:
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


A rare disorder/difference of sex development (DSD) associated with a numerical sex chromosome abnormality resulting from Y-chromosome mosaicism and associated to abnormal gonadal development and features of Turner-Syndrome.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The clinical manifestations are highly variable, ranging from partial virilization and ambiguous genitalia at birth to people with a completely male or female phenotype. The most common feature of 45,X/46,XY mixed gonadal dysgenesis (MGD) is asymmetric development of testes, often with a dysgenic testis on one side and a streak gonad on the other. Asymmetry of the external and internal genitalia may also be present. Infants may have frank genital ambiguity and sex assignment may be postponed or left open. Some infants may present with cryptorchidism, partial testicular dysgenesis, and hypospadias... Affected children may show manifestations of other clinical features of Turner syndrome (e.g. short stature, kidney malformations etc.). There may be persistence of Müllerian structures, depending on the degree of dysgenesis. The uterus is of variable size and the degree of differentiation of the internal genitalia varies. Short stature may be present in both sexes and patients are at increased risk of developing gonadoblastomas and dysgerminomas. Global development is normal.
Etiology
Patients with 45,X/46,XY mixed gonadal dysgenesis (45,X/46,XY MGD) mostly have a 45,X/46,XY karyotype, with the phenotype of the gonads and the external genitalia depending on the proportion of monosomic cells. The presence of 45,X cell lines is frequently associated with Y chromosome rearrangements (commonly dicentric and ring Y chromosomes), which may also have an impact on the phenotype. All cases are sporadic. Several genotype-phenotype correlations have been established: partial expression of the SRY gene (leading to partial testicular dysgenesis and resulting in diminished testosterone synthesis and hence to the androgenization deficit), presence of the gonadoblastoma (TSPY1) locus on the Y-chromosome in females (associated with an increased risk for the development of neoplasms), and dosage loss of the SHOX gene leading to short stature. The formation of the uterus is due to lack of production of anti-Müllerian hormone.
Diagnostic methods
Diagnosis is made by cytogenetic analysis of chromosome status. Karyotype analysis may be conducted prenatally after amniocentesis or chorionic villus sampling, postnatally in patients with ambiguous genitalia, or later in life in patients with fertility problems.
Differential diagnosis
The differential diagnosis should include 46,XY partial gonadal dysgenesis (46,XY PGD) and syndromic 46,XY gonadal dysgenesis (such as Frasier syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency).
Antenatal diagnosis
Antenatal diagnosis is possible if a genital atypia is suspected with imaging.
Genetic counseling
Genetic counseling should be provided to parents with a prenatal diagnosis of 45,X/46,XY mosaicism but is complicated by the broad phenotypic spectrum associated with this condition.
Management and treatment
Multidisciplinary management in a center for DSDs should be favored in cases of obvious ambiguous genitalia, allowing informed decisions for sex assignment and planning of procedures. Surgical reconstruction of genital status may be performed in due course if medically necessary and legally approved. Gonadectomy may be considered in patients with a female sex assignment due to the increased risk of gonadoblastoma. In patients with male sex assignment, orchidopexy is required for fixation of the testes in the scrotum and functional assessment including biopsy may be recommended at the time of puberty. Usually, the more dysgenic gonad needs to be removed. Due to the increased risk of malignancy, ultrasound of the gonads should be performed on a regular basis. In some patients, the possibility of growth hormone treatment needs to be discussed if short stature is found.
Prognosis
Clinical and psychological outcomes depend on the quality of care and level support provided.

                            Last update:
                            June 2022

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

                                * European Reference Network


46,XX difference of sex development-anorectal anomalies syndrome

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

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.


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.

Summary:
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

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,XX ovotesticular difference of sex development

A rare difference of sex development (DSD) characterized by histologically confirmed testicular and ovarian tissue in an individual with a 46,XX karyotype.

Summary:
Epidemiology
Estimated prevalence is approximately 1/20,000 births. The disorder may account for less than 3-10% of all DSD.
Clinical description
About 20% of affected individuals are diagnosed before 5 years of age. Diagnosis is commonly made during the neonatal period due to atypical genitalia. Some present later with abnormal pubertal development. Signs include: lower abdominal pain, gynecomastia, inguinal hernia, an inguinoscrotal mass, cryptorchidism or amenorrhea/periodic hematuria depending on sex assignment. Most affected individuals have female internal genitalia (uterus, hemi-uterus or rudimentary uterus). Development of external genitalia ranges from apparent female to male genitalia with hypospadias or isolated bilaterally undescended ovotestes (gonads containing ovarian and testicular elements). Infertility is common in men whereas women have some potential for fertility. Malignant gonadal tumors are rare (less than 3% of cases).
Etiology
The cause of 46,XX ovotesticular DSD is not elucidated for the majority of cases. A small proportion of individuals have a translocation of a Y chromosome fragment, including the SRY gene, to an X or another chromosome but most individuals (65%) are SRY negative. Copy number variations, resulting in duplication or deletion of regulatory genes, have been described for SOX9 (4 families), SOX3 (1 individual) and NR0B1 (1 individual). A recurrent NR5A1 variant has been reported in a number of unrelated individuals. Some individuals may have a chromosomal mosacism or a chimerism that results in the presence of Y chromosome containing cells in the gonad.
Diagnostic methods
The assessment and diagnosis of DSD is complex. Consensus guidelines recommend referral to a specialist center for examination and treatment. Initial investigations include chromosome analysis and an ultrasound scan to check the internal reproductive organs. Patients who present later in life have higher differentiation of genitalia. Diagnosis requires careful anatomical assessment via imaging modalities and/or laparoscopy. Biochemical endocrine investigation, cytogenetic and molecular genetic tests are required. Definitive diagnosis is based on gonadal histology (testicular and ovarian tissue).
Differential diagnosis
Differential diagnoses include other DSD, including mixed gonadal dysgenesis and 46,XX testicular DSD. NR2F2 gene variants have been described in individuals with a 46,XX testicular / ovotesticular DSD phenotype associated with cardiac defects, some with congenital diaphramatic hernia and blepharophimosis-ptosis-epicanthis inversus. Rarely, others include palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (caused by biallelic RSPO1 gene variants), SERKAL syndrome (recessive WNT4 variants).
Antenatal diagnosis
Prenatal diagnosis may be possible following demonstration of atypical genitalia on ultrasound and amniocentesis revealing a 46,XX karyotype.
Genetic counseling
Genetic counseling should be offered to families of affected children. Recurrence risk depends on the type of genetic alteration found. The majority arise as de novo gene variants.
Management and treatment
The patient and family must be provided with psychological support. Other treatments primarily involve hormone replacement. The need for and timing of surgical treatment is complex, depending on sex assignment and gonadal configuration. Management needs to balance the risks and benefits of gonadectomy and reconstructive surgery.
Prognosis
Patients usually have normal life expectancy.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Faisal AHMED  - Pr Kenneth MCELREAVEY  - Dr Ruth MCGOWAN  - Pr Edward TOBIAS


46,XX testicular difference of sex development

A rare difference of sex development (DSD) associated with a 46, XX karyotype and characterized by male external genitalia, ranging from normal to atypical with associated testosterone deficiency.

Summary:
Epidemiology
The estimated prevalence is 1/20,000 males.
Clinical description
The clinical phenotype is variable, with features that include: normal male external to atypical genitalia, undescended testes with absent Müllerian structures and infertility. Presentation depends on the presence of the SRY gene (sex determining region of the Y chromosome). SRY positive cases (80-90%) are usually otherwise normal men who present after puberty with short stature, normal pubic hair and penile size but small testes, gynecomastia and azoospermia-related sterility. Undescended testes and hypospadias are also reported. There are usually no concerns about gender role and identity. SRY negative individuals (10-20%) usually present at birth with features such as penoscrotal hypospadias and undescended testes. Long-term complications due to male hypogonadism include: low libido, erectile dysfunction, decreased secondary sexual characteristics, osteopenia and depression.
Etiology
In most patients, the condition is caused by translocation of a small Y chromosome fragment, including SRY onto an X or other chromosome. In SRY negative cases, copy number variations, involving regulatory genes (SOX3, SOX9) and a common recurrent NR5A1 variant are reported.
Diagnostic methods
Diagnosis is based on clinical signs and endocrine testing showing hypergonadotrophic hypogonadism and cytogenetic or molecular testing (SNP array) confirming an XX genome. Fluorescence hybridization (FISH) or polymerase chain reaction (PCR) techniques may detect the SRY gene.
Differential diagnosis
The main differential diagnoses are 45,X/46,XY mixed gonadal dysgenesis, 47,XXY Klinefelter syndrome, 46,XX ovotesticular DSD and sex chromosome mosaicisms. NR2F2 gene variants have been described in individuals with a 46,XX testicular / ovotesticular DSD phenotype associated with cardiac defects, some with congenital diaphramatic hernia and blepharophimosis-ptosis-epicanthis inversus. Rarely, others include palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (caused by biallelic RSPO1 gene variants), SERKAL syndrome (recessive WNT4 variants) and microphthalmia with linear skin defects (MIDAS) syndrome.
Antenatal diagnosis
Prenatal testing in pregnancies may be possible if the underlying genetic cause has been identified.
Genetic counseling
Genetic counseling should be offered to affected individuals and their families. Recurrence risk depends on the type of genetic alteration found. SRY positive cases are generally not inherited because this is usually associated with infertility. In SRY negative cases, the pattern of inheritance depends on the genetic cause, if known.
Management and treatment
The mainstay of treatment is testosterone replacement therapy to correct hormonal imbalance, prevent gynecomastia and to induce development of male secondary sex characteristics. Hypergonadotrophic hypogonadism is uncommon prior to adulthood. Reduction mammoplasty may be considered in some cases. Psychological support and timely referral to an assisted conception service should be offered.
Prognosis
Management of male hypogonadism reduces complications. Affected individuals are typically infertile. Tumorigenic risk is low.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Faisal AHMED  - Pr Kenneth MCELREAVEY  - Dr Ruth MCGOWAN  - Pr Edward TOBIAS


A rare disorder/difference of sex development (DSD) associated with absence in gonadal development that results in the presence of female appearing external and internal genitalia in presence of a 46,XY karyotype.

Summary:
Epidemiology
The prevalence of 46,XY complete gonadal dysgenesis ( 46,XY CGD) is unknown.
Clinical description
Patients are born with typical female appearing external genitalia as well as the presence of a uterus and fallopian tubes. They often present during adolescence or early adulthood with lack of pubertal development although adrenarche is normal. Completely undeveloped streak gonads are present and are associated with an increased risk of abdominal tumors (most commonly dysgerminoma), which may be the presenting feature in some cases. Stature is normal or above normal, and features of Turner syndrome are absent.
Etiology
Although the etiology is not completely understood, 46,XY CGD results from failure of testicular development due to disruption of the underlying genetic pathways. Several genes have been implicated: SRY (gene deletion or loss-of-function mutations; Yp11.3), NR5A1 (9q33) and DHH (homozygous or compound heterozygous mutations; 12q13.1). In addition, patients with partial duplications of Xp (including the NR0B1 gene) and chromosome 9p deletions (involving the DMRT1) may also present with isolated 46, XY CGD. Mutations in the CBX2 gene have been rarely reported, namely in a patient with development of ovarian tissue despite 46,XY karyotype. Mutations in the MAP3K1 gene (5q11.2) that cause downstream alterations in the MAP kinase signaling pathway have recently been identified in two familial and two sporadic cases. Of high clinical relevance, 46,XY CGD is a feature of Frasier syndrome (caused by WT1 variants). Environmental factors (maternal progesterone intake during pregnancy), and impaired prenatal growth have also been associated with 46,XY CGD. In the majority of cases, the genetic etiology remains unclear.
Diagnostic methods
Diagnosis is made on the basis of the clinical findings together with cytogenetic analysis, endocrine investigations, molecular genetic studies, and sometimes surgical exploration with biopsy and removal of streak gonads.
Differential diagnosis
The differential diagnosis should include hypergonadotropic ovarian dysgenesis (46,XX GD) and all forms of syndromic 46,XY CGD (for example, Frasier syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency).
Antenatal diagnosis
Prenatal diagnosis is feasible for families in which the genetic anomaly has been confirmed but is only recommended in syndromic cases.
Genetic counseling
Although some cases of 46,XY CGD occur sporadically, genetic counseling may be offered to affected families and should be adapted depending on the mode of inheritance associated with the genetic anomaly identified.
Management and treatment
Management may involve removal of streak gonadal tissue as there is a risk for malignancy, which may depend on the underlying etiology. Possible associated health issues (e.g. associated malformations) need to be addressed according to the genetic diagnosis. Hormone substitution is recommended at the time of puberty. Psychological support should also be offered to patients and their families in a specialized DSD-center. Infertility is an important management issue; however, pregnancy may be feasible through zygote egg donation.
Prognosis
With appropriate management, the risk of malignancy is low and the psychological and clinical outcome for patients is good.

                            Last update:
                            June 2022

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

                                * European Reference Network


46,XY difference of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency

A rare difference of sex development characterized by 17-beta hydroxysteroid dehydrogenase 3 deficiency that affects individuals with a 46,XY karyotype leading to underandrogenization of the genitalia.

Summary:
Epidemiology
Estimated prevalence at birth has been reported to be 1/147,000 in the Netherlands; the prevalence may be higher elsewhere, especially in populations with high consanguinity.
Clinical description
The clinical presentation is variable. Atypical external genitalia with variable phallic size and posterior labioscrotal fusion are often noticed at birth. Patients with typical female-appearing external genitalia may present with inguinal hernia in childhood. Although some patients, with less severe enzyme defiency, are assigned males at birth, affected individuals are often assigned females at birth. However, at puberty, a portion of these patients develop signs of unusual androgenization (phallic enlargement, male secondary sexual characteristics) as the result of increased testosterone (due to conversion of androstenedione by 17-beta-hydroxysteroid dehydrogenase isoenzymes). Testes can be abdominal, inguinal, or in the labioscrotal folds. The internal urogenital tract is developed to a variable extent, and Müllerian structures are absent. All affected individuals are infertile.
Etiology
The condition is caused by mutations in the HSD17B3 gene (9q22) encoding an enzyme expressed predominantly in the testes that converts androstenedione to testosterone. The variable clinical phenotype may be related to partial activity of the enzyme or activity of isoenzymes.
Diagnostic methods
Hormonal evaluation demonstrates increased androstenedione and low testosterone levels, with an elevated androstenedione/testosterone ratio. The Sertoli cell markers, serum AMH and inhibin B, are usually in the typical age-related reference range for males. Before puberty, an hCG (human chorionic gonadotropin) stimulation test is often necessary for diagnosis, since basal levels may be uninformative. Therefore, recent consensus statements recommend the molecular genetic analysis of the HSD17B3 gene as a primary diagnostic approach.
Differential diagnosis
The differential diagnosis includes disorders of androgen synthesis such as 5-alpha-reductase 2 deficiency, complete and partial androgen insensitivity syndromes and partial gonadal dysgenesis (caused by NR5A1 mutations for example).
Antenatal diagnosis
Prenatal diagnosis is available for the kindred of affected patients if causal pathogenic variants have been identified. Atypical fetal genitalia may be seen on prenatal ultrasound.
Genetic counseling
The condition follows an autosomal recessive inheritance pattern. Parents of an affected individual should be informed that there is a 25% of chance of having an affected child at each pregnancy.
Management and treatment
If diagnosed at birth, gender assignment should be discussed openly with the family and an evaluation should be done at a DSD center. Any genital surgery demands a thorough assessment and is restricted in several countries in childhood. Early gonadectomy is unnecessary. Depending on gender identity development, some adolescents may demand a gender change whereas others may request treatment to prevent pubertal androgenization and to induce female puberty.
Prognosis
Life expectancy and overall morbidity (other than related to untreated hormone deficiency) are not altered. The impact on genital development, puberty and adult sexual functioning is usually severe and may require endocrine and/or surgical treatment, as well as psychological counseling.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Dr S.E. [Sabine] HANNEMA  - Pr Olaf HIORT | Endo-ERN* - Pr Luca PERSANI

                                * European Reference Network


46,XY difference of sex development due to 5-alpha-reductase 2 deficiency

A rare difference of sex development (DSD) due to a defect in metabolizing testosterone to dihydrotestosterone and characterized by incomplete intrauterine masculinization which ranges from a female genitalia with a blind vaginal pouch to a fully male phenotype with pseudovaginal posterior hypospadias and micropenis.

Summary:
Epidemiology
The disease has been described in large pedigrees from the Dominican Republic, Southern Lebanon and the Eastern Highlands Province of Papua New Guinea. It is relatively rare among Caucasians, but is recognized as a significant cause of DSD and mutational analysis is part of initial investigations.
Clinical description
Patients present at birth with characteristics of dihydrotestosterone (DHT) deficiency, such as posterior hypospadias, micropenis/clitoris-like phallus, bifid scrotum, cryptorchid testes (with normal or reduced spermatogenesis), and rudimentary prostate. The clinical spectrum is heterogeneous, ranging from a female with a blind vaginal pouch to a fully male phenotype with hypospadias and micropenis. Two-thirds of patients are initially assigned female gender, and thus clinical presentation maybe later during childhood with abnormal genitalia or during puberty with scarce facial and body hair (with normal sebum production) and virilization without breast development. Wolffian duct differentiation (testosterone-dependent) and regression of Müllerian structures (AMH-dependent) are not involved.
Etiology
The disease is caused by mutations in the SRD5A2-gene (2p23.1) leading to a reduced or absent function of the steroid 5 alpha-reductase type 2 enzyme which converts testosterone into DHT in the external genitalia. As a result, male differentiation fails to occur during fetal development, despite high circulating testosterone levels. Manifestations at birth vary according to the levels of residual enzymatic function.
Diagnostic methods
Diagnostic criteria include genital ambiguity, a family history of DSD, and genital/karyotype discordance. Biochemical findings reveal increase in the testosterone/DHT ratio after human chorionic gonadotropin stimulation and normal testosterone and anti-Müllerian hormone concentration. Diagnosis also relies on 5-alpha-reductase activity assessment using the urinary steroid profiling (ratio of androsterone to etiocholanolone and 5-alpha-tetrahydrocortisol/tetrahydrocortisol and 5-alpha-tetrahydrocorticosterone to tetrahydrocorticosterone below the lower limit of normal). Nowadays, the diagnosis is most commonly determined directly by genetic screening.
Differential diagnosis
Differential diagnosis includes many other causes of severe hypospadias like partial androgen insensitivity syndrome, 17-beta-hydroxysteroid dehydrogenase 3 deficiency and Leydig cell hypoplasia.
Antenatal diagnosis
Prenatal diagnosis with ultrasound is uncommon but may occur in families with a previously diagnosed child.
Genetic counseling
Transmission is autosomal recessive and genetic counseling should be offered to at-risk couples. The parents are almost always carriers and without symptoms, but 25% of their boys will be affected. Girls with 46,XX karyotype and who are homozygous for mutations in the gene, will have no symptoms, but will transmit the mutation to their children.
Management and treatment
For patients raised as male, the main concern is to keep the testis for later hormone production. Topical DHT cream on the pubic area can be applied neonatally after diagnosis at least during the minipuberty. Surgical repair of hypospadias (chordee correction, urethral reconstruction and orchidopexia with or without scrotalplasty,) should be performed at 6-18 months of age. For patients raised as female, management may include surgical correction of the external genitalia (vaginal opening into the perineum with early separation of the vagina and urethra), early removal of gonadal tissue to prevent masculinization before puberty, clitoral reduction (if severe masculinization) and cyclic hormonal therapy at puberty for development of secondary sexual characteristics. Choosing a female sex is nowadays only an option in XY children with a total deficiency.
Prognosis
The risk of gonadal tumors in individuals with SRD5A2 mutations is quite low. Prostate diseases (prostate cancer, benign prostate hyperplasia) have not been reported in affected males. Most men are infertile due to the small prostate gland causing diminished semen volume and lack of spontaneous fertility; however, artificial reproductive techniques are a possibility.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Agneta NORDENSKJÖLD


46,XY difference of sex development due to isolated 17,20-lyase deficiency

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.


46,XY difference of sex development-adrenal insufficiency due to CYP11A1 deficiency

A rare, genetic, developmental defect during embryogenesis disorder characterized by severe, early-onset, salt-wasting adrenal insufficiency and ambiguous/female external genitalia (irrespective of chromosomal sex) due to mutations in the CYP11A1 gene. Milder cases may present delayed onset of adrenal gland dysfunction and genitalia phenotype may range from normal male to female in individuals with 46,XY karyotype. Imaging studies reveal hypoplastic/absent adrenal glands and biochemical findings include low serum cortisol, mineralocorticoids, androgens, and sodium, with elevated potassium levels.


46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome is a rare, genetic, developmental defect during embryogenesis disorder characterized by partial (unilateral testis, persistence of Müllerian duct structures) or complete (streak gonads only) gonadal dysgenesis, usually manifesting with primary amenorrhea in individuals with female phenotype but 46,XY karyotype, and sensorimotor dysmyelinating minifascicular polyneuropathy, which presents with numbness, weakness, exercise-induced muscle cramps, sensory disturbances and reduced/absent deep tendon reflexes. Germ cell tumors (seminoma, dysgerminoma, gonadoblastoma) may develop from the gonadal tissue.


46,XY ovotesticular difference of sex development

46,XY ovotesticular disorder of sex development is a rare, genetic disorder of sex development characterized by either the coexistence of both male and female reproductive gonads or, more frequently, by the presence of one or both gonads containing a mixture of both testicular and ovarian tissue (ovotestes) in an individual with a normal male 46, XY karyotype. External genitalia are usually ambiguous, but can range from normal male to normal female and if a uterus and/or fallopian tubes are present, they are generally hypoplastic. Cryptorchidism, hypospadias, infertility and increased risk of gonadal tumours are frequently associated.


A rare disorder/difference of sex development (DSD) characterized by atypical gonadal development that results in genital ambiguity of variable degree ranging from almost female phenotype to almost male phenotype in a patient carrying a 46,XY karyotype.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
46,XY partial gonadal dysgenesis (46,XY PGD) is characterized by ambiguous external genitalia with or without Müllerian structures. The degree of genital ambiguity varies along a spectrum, ranging from an almost female phenotype with clitoromegaly at one extreme to an almost male phenotype with isolated hypospadias at the other. Many patients present ambiguous genitalia or severe micropenis and cryptorchidism associated with complete regression of testicular tissue in one or both sides. Testicular regression syndrome (ETRS) is considered as part of the clinical spectrum of 46,XY PGD. Patients with NR5A1 variants can have adrenal insufficiency. Gonadoblastomas or dysgerminomas may occur in a significant proportion of patients, but may depend on the genetic origin.
Etiology
46,XY PGD is a heterogeneous disorder associated with partial absence of both Leydig cell and Sertoli cell function that may result from a variety of genetic events. Rarely, deletions or point mutations in the SRY gene or dose sensitive sex locus (NR0B1) duplication on the X chromosome have been described. Most SRY mutations are de novo mutations, however some cases of X-linked inheritance have been observed. More important are mutations in steroidogenic factor 1 (NR5A1; SF-1). SF-1 is a nuclear receptor and regulator of multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Therefore, affected patients may also have adrenal insufficiency. 46,XY PGD may be a feature of many syndromes (e.g Denys-Drash syndrome) and other genetic conditions.
Diagnostic methods
Diagnosis is made on the basis of clinical findings with cytogenic analysis, endocrine investigations, molecular genetic studies, and sometimes surgical exploration with biopsy.
Differential diagnosis
Differential diagnoses include all forms of syndromic 46,XY gonadal dysgenesis (for example, Denys-Drash syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency) and similar phenotypes that can also result from a 45,X/46,XY karyotype, known as 45,X/46,XY mixed gonadal dysgenesis (45,X/46,XY MGD). The absence of a 45,X lineage is of importance for the management and prognosis.
Antenatal diagnosis
Antenatal diagnosis is possible if a genital malformation is suspected with imaging and if a familial background exists.
Genetic counseling
Genetic counseling is mandatory.
Management and treatment
Management of patients requires a multi-disciplinary team in a designated DSD centre. Psychological evaluation and counseling of parents is necessary. The determination of social sex should consider etiological diagnosis, clinical evaluation, ethnic traditions, sexual identity and the acceptance of assigned social sex by the parents. Hormone therapy in patients with female social sex at the time of puberty is based on estrogen and progesterone for those patients where uterus is present in order to induce menses, and estrogen alone in patients without a uterus. Androgen replacement, including testosterone injections, may be appropriate for patients who choose a male social sex in adolescence. Surgery may be considered to allow sex appropriate functionality. This may require legal approval in some countries. Previously, gonadectomy was widely performed in children assigned to female sex, but is nowadays often postponed to allow an informed consent policy. However, due to the increased risk for the development of gonadal tumors, regular clinical assessment and diagnostic visualization of the gonads should be recommended.
Prognosis
With early diagnosis, surgery and hormone treatment can result in good outcome, both functionally and phenotypically. Infertility is almost always present.

                            Last update:
                            June 2022

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

                                * European Reference Network


A rare sex chromosome aneuploidy where males receive an additional Y chromosome, that is characterized clinically by tall stature evident from childhood, macrocephaly, facial features (mild hypertelorism, low set ears, a mildly flat malar region), speech delay and an increased risk for social and emotional difficulties, attention deficit hyperactive disorder and autistic spectrum disorder.


The 48,XXXY syndrome represents a chromosomal anomaly of the aneuploidic type characterized by the presence of two extra X chromosomes in males.

Summary:
Epidemiology
There is an annual incidence of 1/50,000 male births.
Clinical description
The 48,XXXY syndrome differs from Klinefelter syndrome by the presence of moderate intellectual deficit (average IQ of 50), more marked genital hypoplasia (microorchidism, micropenis, hypoplasia of the scrotum) and by more frequently observed facial dysmorphism (flat nose, epicanthus, prognathism, short neck, hypertelorism, facial asymmetry). Other dysmorphic characteristics (clinodactyly of the fifth finger, coxa valga, etc.) are often associated with this syndrome. Congenital skeletal malformations (kyphoscoliosis, radioulnar synostosis, epiphyseal dysplasia) canalso be present in addition to genital anomalies (cryptorchidism) and gynecomastia. With age, other manifestations can also appear such as arthropathies, obesity, behavioral problems (hyperactivity, irritability, anxiety, immaturity, passivity, anger, communication and socialization problems) and language retardation.
Etiology
The most likely etiology is the non disjunction of homologous chromosomes (during the first meiotic division) or sister chromatids (during the second meiotic division) in the parental germ cells. There is no known factor responsible for or favoring the development of this syndrome.
Diagnostic methods
The metaphase karyotype allows for the confirmation of a clinical diagnosis. Mosaicism with other polygonosomies is not uncommon (48,XXXY/ 48,XXYY/ 49,XXXXY).
Differential diagnosis
Differential diagnoses include other aneuploidies, such as Klinefelter syndrome (47,XXY), 48,XXYY syndrome and 49,XXXXY syndrome (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible by amniocentesis.
Genetic counseling
The risk of recurrence is very low as cases of 48,XXXY are sporadic.
Management and treatment
Management needs to be handled by a multidisciplinary team and includes the treatment of cardiac and skeletal malformations, management of sensory, neurological, hormonal (testosterone-based hormone therapy), metabolic (supervising obesity), psychological and psychiatric care and dental follow-up.
Prognosis
Patients have an essentially normal life expectancy but will need to attend regular medical visits, in particular for their endocrine and infectious problems, and to undergo regular psychiatric monitoring.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Carole CORSINI  - Pr Pierre SARDA


A rare sex chromosome number anomaly disorder characterized, genetically, by the presence of an extra X and Y chromosome in males and, clinically, by tall stature, dysfunctional testes associated with infertility and insufficient testosterone production, cognitive, affective and social functioning impairments, global developmental delay, and an increased risk of congenital malformations.

Summary:
Epidemiology
The estimated prevalence is between 1/18,000 to 1/50,000 male births.
Clinical description
Presentation is often in infancy or early childhood with hypotonia and global development delay, sometimes accompanied by mild dysmorphic facies, plagiocephaly, and flat feet. Testicular hypogonadism, starting in adolescence and persisting throughout adulthood, is nearly universal. Cryptorchidism, micropenis, and gynecomastia have been occasionally reported. Overall, cognitive abilities tend to be in the borderline range (70-80) with about 1/3 of males with full scale IQ in the intellectually disabled range. Significantly lower verbal reasoning skills are often present. Relative to IQ, adaptive functioning is significantly impaired, with common deficits in communication, social skills, self-care, and self-direction. Many medical conditions are frequently associated, including significant dental problems (~90%), tremor (~60% of adults), asthma/allergies (~60%), skeletal anomalies (club foot, radioulnar synostosis, prominent elbows with cubitus varus, scoliosis, and kyphosis), type 2 diabetes (~20% in adulthood), thrombosis (~18%), epilepsy (~15%), strabismus (~15%), gastrointestinal problems (feeding intolerance, reflux, constipation), congenital heart defects, and renal abnormalities. Non-specific dysmorphic features may include epicanthal folds, hypertelorism, and clinodactyly. Behavioral patterns can include characteristics of attention-deficit/hyperactivity disorder and autism spectrum disorder, in addition to mood instability, anxiety, obsessive-compulsive behaviors, and emotional immaturity.
Etiology
48,XXYY syndrome results from a nondisjunction event of sex chromosomes during spermatogenesis or, less often, from post-zygotic mitotic nondisjunction during cell division. There are no known predisposing factors.
Diagnostic methods
Diagnosis is often made during childhood evaluation of physical and/or developmental concerns. Diagnosis is confirmed with standard karyotype or chromosomal microarray.
Differential diagnosis
Main differential diagnoses include 47,XXY syndrome; 48,XXXY syndrome; 49,XXXXY syndrome; 45,X/46,XY mosaicism and 46,XX males. Other possible overlapping conditions include Fragile X, Jacob, Prader-Willi, Soto, Börjeson-Forssman Lehman, Weaver, and Cohen syndromes.
Antenatal diagnosis
Non-invasive prenatal screening through cell-free fetal DNA can identify a fetus with 48,XXYY but this test is not diagnostic. Antenatal diagnosis is possible by amniocentesis or chorionic villus sampling.
Genetic counseling
48,XXYY is typically due to a sporadic aneuploidy event with an estimated recurrence risk of <1%. Genetic counseling should include a review of the potential physical, medical, developmental and psychological features.
Management and treatment
Comprehensive interdisciplinary care is important to evaluate and manage the associated developmental, medical, and psychological conditions. A thorough physical exam, renal ultrasound and echocardiography should be performed to evaluate for congenital defects. Vision/hearing screenings and routine dental care are important throughout life. Comorbidities, such as asthma and epilepsy, should be diagnosed and managed as they would be in individuals without 48,XXYY. Pubertal examinations and serum hormone profiles should be monitored beginning around age 10, and testosterone supplementation should be considered for hypogonadism. Annual screening for hyperlipidemia, diabetes, and autoimmune thyroid disease is recommended starting in adolescence. Comprehensive, interdisciplinary neurodevelopmental and behavioral evaluation is warranted throughout childhood. Interventions targeting psychological functioning (including emotional and behavioral disorders) and speech/language, motor, and self-care skills should be evidence-based and individualized. School- and community-based supports and services frequently form part of the treatment plan.
Prognosis
While there is no cure, with appropriate treatment for associated medical and psychiatric conditions, life expectancy is typically normal. Health-related quality of life and degree of independence varies depending on the severity of symptoms and access to appropriate health care and support services.

                            Last update:
                            January 2019

                            - Expert reviewer(s):
                             Catherine BUCHANAN  - Dr Shanlee DAVIS  - Dr Susan HOWELL  - Dr Nicole TARTAGLIA  - Dr Adrianne VILLAGOMEZ


A rare Y chromosome number anomaly that affects only males and is characterized by mild-moderate developmental delay (especially speech), normal to mild intellectual disability, large, irregular teeth with poor enamel, tall stature and acne. Radioulnar synostosis and clinodactyly have also been associated. Boys generally present normal genitalia, while hypogonadism and infertility is frequently reported in adult males.


The 49,XXXXY syndrome represents a chromosomal anomaly of the aneuploidic type characterized by the presence of three extra X chromosomes in males.

Summary:
Epidemiology
It has an annual incidence of 1/85,000 to 1/100,000 male births.
Clinical description
The 49,XXXXY syndrome differs from Klinefelter syndrome by its variable IQ with an often subtle intellectual deficit in childhood but a progressive (moderate to severe) deterioration with age (IQ varying between 70 and 20), by the absence of tall stature with delayed growth often already visible in utero and under the third percentile after birth, and sometimes by a small stature and a deficit in growth hormones. Hypogonadism is severe with a micropenis, microorchidism, hypoplasia of the scrotum and cryptorchidism. Gynecomastia is uncommon. Remarkable facial dysmorphism (hypertelorism, large flat nose with a depressed nasal curvature, upslanting palpebral fissures, epicanthus, prognathism, folded-over ears, short neck) and other dysmorphic characteristics (cubitus valgus, flat feet, clinodactyly of the fifth finger, joint laxity) appear frequently. Congenital heart defects (arterial canal) as well as skeletal defects (radioulnar synostosis, epiphyseal dysplasia, coxa valga, kyphoscoliosis, hip and knee dislocation), cerebral (hypoplastic corpus callosum, arhinencephaly) and renal defects (renal hypoplasia) can also be present. Axial hypotonia is often seen in children. With age, the intellectual deficit worsens and is associated with a major delay in language development. Strabismus or severe and progressive myopia can occur which can lead to declining vision. Behavioral problems such as shyness can also become apparent.
Etiology
The etiology is the non disjunction of homologous chromosomes (during the first meiotic division) or of sister chromatids (during the second meiotic division) in the maternal germ cells. There is no known factor responsible for or favoring the appearance of this syndrome.
Diagnostic methods
The metaphase karyotype allows for the confirmation of a clinical diagnosis.
Antenatal diagnosis
Antenatal diagnosis is possible by an amniocentesis screening for a wide range of conditions.
Genetic counseling
The risk of recurrence is very unlikely as cases of 49,XXXXY are sporadic.
Management and treatment
Management needs to be handled by a multidisciplinary team and includes the treatment of cardiac and skeletal defects, the monitoring of psychomotor development with physiotherapy, psychomotricity, speech therapy, orthopedic and sensory management (ophthalmological examination), neurological, hormonal (if necessary) and psychological care and regular dental follow-up.
Prognosis
Patients have an essentially normal life expectancy but will need to attend regular medical visits.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Carole CORSINI  - Pr Pierre SARDA


49,XXXYY syndrome is a rare gonosome anomaly syndrome characterized by a eunuchoid habitus with gynecoid fat distribution and shape, normal to tall stature, moderate to severe intellectual disability, distinctive facial features (e.g. prominent forehead, epicanthic folds, broad nasal bridge, prognathism), gynecomastia, hypogonadism, cryptorchidism, small penis and behavioral abnormalities (incl. solitary, passive disposition but prone to aggressive outbursts, autistic). Skeletal malformations, such as delayed bone age, fifth finger clinodactyly, elbow malformations and slow molar development, may also be associated.


A rare Y chromosome number anomaly with a variable phenotype mainly characterized by moderate to severe intellectual disability, speech delay, hypotonia, and mild dysmorphic features, including facial asymmetry, hypertelorism, bilateral low set 'lop' ears, and micrognatia. Skeletal abnormalities (such as skull deformities, radioulnar synostosis, elbow flexion, clinodactyly, brachydactyly) and behavourial problems have also been associated with this condition. Genitalia are normal at birth, although hypogonadism and azoospermia has been reported in adults.


A rare hypomyelinating leukodystrophy disorder characterized by the association of dental abnormalities (delayed dentition, abnormal order of dentition, hypodontia), hypogonadotropic hypogonadism, and hypomyelinating leukodystrophy manifesting with neurodevelopmental delay or regression and/or progressive cerebellar symptoms.

Summary:
Epidemiology
To date, more than 200 cases have been reported worldwide.
Clinical description
Age of onset typically ranges from infancy to childhood but exceptionally may occur in late adolescence or early adulthood. The clinical phenotype is variable with about half of affected individuals presenting global developmental delay, which usually presents in infancy. Cerebellar signs frequently include intention tremor, dysmetria, absence of smooth pursuit and gaze-evoked nystagmus and, more variably, gait ataxia and vertical gaze limitation. Pyramidal signs are typically absent in young children and may develop slowly in older patients. Extrapyramidal signs, typically dystonia, are prominent in only a few patients. Wheelchair dependence typically occurs from the end of the first decade, although half of patients remain ambulatory as adults. Cognition varies from normal to learning difficulties or mild to moderate intellectual disability (most frequent), with slow deterioration in the second decade. Expressive language and swallowing is present until late but deteriorates over time. Dental abnormalities include delayed dentition with abnormal order of deciduous teeth eruption, hypodontia and, less frequently, natal teeth. Delayed puberty or primary amenorrhea is frequent. Most patients have high myopia; optic atrophy is present in older individuals. About half of patients have short stature, and may have growth hormone deficiency. Central hypothyroidism is present in a few patients. Brain magnetic resonance imaging (MRI) shows hypomyelination along with relative T2 hypointensity of optic radiation, posterior limb of internal capsule, anterolateral thalamus, and dentate nucleus.
Etiology
Mutations of the genes encoding POLR3 (RNA polymerase III) subunits, POLR3A, POLR3B and POLR1C, have been identified. POLR3 is an enzyme responsible for transcription of specific noncoding small RNAs involved in the regulation of transcription, RNA processing, and translation. It is suggested that these mutations lead to abnormal POLR3 function and abnormal production of proteins important for development of central nervous system white matter. Despite the overlap in causal genes, no genotype-phenotype correlation has been identified.
Diagnostic methods
Diagnosis is suspected based on the clinical presentation and the characteristic hypomyelination findings on brain MRI. Blood tests for levels of thyroid, growth and puberty hormones can be helpful. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Other hypomyelinating leukodystrophies, especially when there are no typical dental abnormalities.
Antenatal diagnosis
Genetic prenatal diagnosis is possible when causal mutations have previously been identified in an affected family.
Genetic counseling
The disease is inherited in an autosomal recessive manner and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, the risk of inheriting the disease is 25%. POLR3A pathogenic variants tend to correspond with an earlier disease onset, more rapid neurological decline and shorter life expectancy than POLR3B pathogenic variants.
Management and treatment
Management and treatment should be multidisciplinary and tailored to the individual. Regular monitoring by an endocrinologist is required. The decision to treat sex and growth hormone deficiency, when present, is individually based. Physical aids and therapy may be required to support motor function. Good dental hygiene and monitoring is recommended to preserve teeth. Regular ophthalmologic follow-up is also necessary, as in most patients, especially with POLR3B mutations, myopia continues to increase.
Prognosis
Prognosis depends primarily on disease severity. At the severe end, affected individuals do not achieve independent walking and have mild to moderate intellectual disability.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr N.I. [Nicole] WOLF


4p16.3 microduplication syndrome is a rare genetic syndrome that results from the partial duplication of the short arm of chromosome 4. It has a highly variable phenotype, principally characterized by psychomotor and language delay, seizures and dysmorphic features such as high forehead with frontal bossing, hypertelorism, prominent glabella, long narrow palpebral fissures, low set ears and short neck. Eye abnormalities (glaucoma, irregular iris pigmentation, hyperopia) have also been reported.


The 4q21 microdeletion syndrome is a newly described syndrome associated with facial dysmorphism, progressive growth restriction, severe intellectual deficit and absent or severely delayed speech.

Summary:
Epidemiology
It has been reported in nine unrelated patients.
Clinical description
The most common facial feature includes high or broad forehead, hypertelorism and short philtrum. Short hands and feet are frequently observed.
Etiology
This microdeletion was identified by comparative genomic hybridisation (CGH) microarray. The critical region encompasses two candidate genes, PRKG2 and RASGEF1B, in which haploinsufficiency could participate to the phenotype.

                            Last update:
                            October 2010

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


A partial deletion of the long arm of chromosome 4 characterized by complex behavioral difficulties, developmental and delay/ intellectual disability, and minor dysmorphic features, including subtle facial asymmetry (most prominent in the mandible), mild hypotelorism, long nasal bridge, small low-set ears, narrow mouth, and mild hand deformities, such as bilateral short 5th metacarpals, and short hands.


A rare intoxication caused by the prolonged, low-dose administration of 5-fluorouracil, which is the mainstay of both adjuvant and advanced-disease chemotherapy regimens in colon cancer. 5-fluorouracil poisoning is characterized by gastrointestinal (nausea, emesis, diarrhea, anorexia, stomatitis) and hematologic (myelosuppression) toxicities as well as mucositis, alopecia and, occasionally, palmar-plantar dysesthesia (more commonly known as hand-foot syndrome). Women have been reported to experience more 5-fluorouracil-related toxicity than men.


A very heterogeneous condition characterized by 5-oxoprolinuria.

Summary:
Epidemiology
It has been detected in eight patients worldwide. All affected patients have been identified because of 5-oxoprolinuria.
Clinical description
Symptoms reported in individual patients include renal stone formation, enterocolitis, intellectual deficiency, neonatal hypoglycemia, microcytic anemia and microcephaly.
Etiology
5-Oxoprolinase catalyses a step in the gamma-glutamyl cycle (glutathione metabolism).
Diagnostic methods
The diagnosis is based on the finding of 5-oxoprolinuria and on the low activity of 5-oxoprolinase.
Differential diagnosis
Other causes of 5-oxoprolinuria include glutathione synthetase deficiency (see this term), diet (certain infant formulas and tomato juice), severe burns, Stevens-Johnson syndrome (see this term), inborn errors of metabolism not involving the gamma-glutamyl cycle, e.g. X-linked ornithine trancarbamylase deficiency, urea cycle defects, or tyrosinemia, as well as homocystinuria (see these terms), drug metabolism (paracetamol, vigabatrin, flucloxacillin, netilmicin), prematurity, malnutrition, pregnancy and nephropatic cystinosis.
Genetic counseling
The disease is transmitted as an autosomal recessive trait.
Management and treatment
No specific treatment has been proposed or tested.
Prognosis
The prognosis is difficult to predict as only eight patients with different clinical symptoms have been described.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Agne LARSSON  - Dr Ellinor RISTOFF


A rare partial autosomal trisomy/tetrasomy characterized by global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, macrocephaly and facial dysmorphism (frontal bossing, short palpebral fissures, low set, dysplastic ears, short or shallow philtrum, high arched or narrow palate, micrognathia). Other associated clinical features include sleep disturbances, seizures, aplasia/hypoplasia of the corpus callosum, skeletal abnormalities (large hands and feet, long fingers and toes, talipes).


The newly described 5q14.3 microdeletion syndrome includes severe intellectual deficit with no speech, stereotypic movements and epilepsy.

Summary:
Epidemiology
To date, fourteen patients have been reported.
Clinical description
Miscellaneous dysmorphic facial features are present in all cases, but some common features are noticed, high and wide forehead, pronounced eyebrows, anteverted nostrils, short and prominent philtrum, down-turned corners of the mouth and small chin. Stereotypic movements and poor eye contact are present in many patients, suggesting the diagnosis of autism spectrum disorder. In most patients brain imaging is reported to be abnormal, including anomalies of the corpus callosum, enlarged ventricles, periventricular white matter, hyperintensities and cortical atrophy.
Etiology
The microdeletion was identified by microarray-based comparative genomic hybridization (CGH). The size of deletions varies, the minimal common deleted region encompasses only MEF2C, suggesting that haploinsufficiency of MEF2C is responsible for the phenotype.

                            Last update:
                            May 2010

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


The newly described 5q35 microduplication syndrome is associated with microcephaly, short stature, developmental delay and delayed bone maturation.

Summary:
Epidemiology
It has been reported in two unrelated patients.
Clinical description
There is no remarkable facial dysmorphism. The clinical picture is opposite to that of patients with Sotos syndrome (macrocephaly, overgrowth and advanced bone age; see this term).
Etiology
This microduplication was identified by microarray-based comparative genomic hybridization (aCGH). The breakpoints of the duplication in both patients map to the proximal and distal low-copy repeats (LCRs), which flank the Sotos critical region. These findings support a non-allelic homologous recombination (NAHR) as the mechanism of duplication, and a dosage effect of the Sotos gene NSD1 (5q35).

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


A rare constitutional hemolytic anemia characterized by a low 6-phosphogluconate dehydrogenase activity in the erythrocytes, which clinically manifests with a well-compensated chronic nonspherocytic hemolytic anemia and transient hemolytic periods with jaundice.


A rare form of hyperphenylalaninemia due to tetrahydropterin (BH4) biosynthesis deficiency, leading to central dopamine and serotonin deficiency, and characterized by infantile-onset neurological disease of variable severity ranging from mild forms with normal neurological development to severe forms with hypotonia, developmental delay, complex movement disorder dominated by dystonia or dystonia parkinsonism.

Summary:
Epidemiology
The global prevalence of BH4 deficiencies remains unknown and great variance can be found among different countries. European newborn screening programs (NBS) reveal that the mean incidence of all hyperphenylalaninemias (HPA) is approximately 1/10,000, with BH4 deficiencies representing 1-2% of cases. 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPSD) is the most frequent of all HPA-associated BH4 deficiencies, representing approximately half of cases.
Clinical description
When left untreated, the deficiency leads to neurological symptoms starting at 4-5 months of age. Very frequent symptoms (>50% of patients) are developmental delay and (axial) hypotonia. Frequent symptoms (25-50% of patients) are hypertonia of the extremities, impaired speech development and being small for gestational age. There are no consistent reports on genotype-phenotype correlation.
Etiology
PTPSD is caused by variants in the PTS gene, which encodes 6-pyruvoyl-tetrahydropterin synthase. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). Therefore, the tetrahydrobiopterin deficiency causes not only HPA, but also a central dopamine and serotonin deficiency.
Diagnostic methods
PTPSD should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. The analysis of pterins in urine or dried blood spot (DBS) in patients and the analysis of dihydropteridine reductase (DHPR) enzyme activity in DBS has to follow in all patients with HPA on NBS. The suspected diagnosis can be further confirmed by genetic evaluation of the PTS gene and/or the measuring of the neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid. Clinical consensus guidelines on the different diagnostic options are available with open access.
Differential diagnosis
The differential diagnosis includes classic phenylketonuria and hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I, pterin-4-alpha-carbinolamine dehydratase, dihydropteridine reductase, and DNAJC12 deficiencies.
Antenatal diagnosis
Prenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.
Genetic counseling
PTPS deficiency is an autosomal recessive genetic disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of sapropterin hydrochlorid) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan). In case of insufficient clinical response or L-dopa-induced hyperkinesia, long-acting dopamine agonists (e.g. pramipexole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors.
Prognosis
Levodopa/carbidopa supplementation drastically improves, often even reconstitutes motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN*

                                * European Reference Network


6p22 microdeletion syndrome is a newly described syndrome associated with a variable clinical phenotype including developmental delay, facial dysmorphism, short neck and diverse malformations.

Summary:
Epidemiology
Eight cases have been reported to date.
Clinical description
The most common facial features include eye anomalies: strabismus, deeply set eyes, and epicanthic folds and ear anomalies such as over-folded helices and low-set ears. This microdeletion was identified by fluorescence in situ hybridization (FISH) or comparative genomic hybridisation (CGH) microarray. Reported patients have deletions of variable size. The critical region for the 6p22 deletion phenotype is 2.2 Mb and encompasses 12 genes; their function is still largely unknown.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


A rare partial deletion of the long arm of chromosome 6 characterized by a variable clinical phenotype that includes a characteristic craniofacial dysmorphism (including microcephaly, broad nose with prominent nasal root and bulbous nasal tip, large ears that may be malformed and low-set, characteristic downturned mouth, and short neck), global development delay, intellectual disability, and variable, non-specific, congenital malformations. Muscular hypotonia, seizures, retinal anomalies, and variable brain abnormalities have been reported in association.


A rare Prader-Willi like syndrome due to an interstitial deletion located at 6q16.1q16.2 and characterized by obesity, hyperphagia, hypotonia, small hands and feet, eye/vision anomalies, and global developmental delay.


6q25 microdeletion syndrome is a recently described syndrome characterized by developmental delay, facial dysmorphism and hearing loss.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 4 patients.
Clinical description
All of them presented with microcephaly, developmental delay, dysmorphic features and hearing loss, whereas two of them had agenesis of the corpus callosum. Dysmorphic features include midface hypoplasia, hypertelorism, broad nasal root and posteriorly rotated ears.
Etiology
This syndrome is caused by an interstitial deletion encompassing 6q25.2-q25.3. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest region of overlap (SRO) of 3.52 Mb.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


7p22.1 microduplication syndrome is a rare chromosomal anomaly syndrome, resulting from a partial interstitial microduplication of the short arm of chromosome 7, characterized by intellectual disability, psychomotor and speech delays, craniofacial dysmorphism (including macrocephaly, frontal bossing, hypertelorism, abnormally slanted palpebral fissures, anteverted nares, low-set ears, microretrognathia) and cryptorchidia. Cardiac (e.g., patent foramen ovale and atrial septal defect), as well as renal, skeletal and ocular abnormalities may also be associated.


7q11.23 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 7 characterized by a highly variable phenotype that typically manifests with mild-moderate intellectual delay (patients could be in the normal range), speech disorders (particularly of expressive language), and distinctive craniofacial features (brachycephaly, broad forehead, straight eyebows, broad nasal tip, short philtrum, thin upper lip and facial asymmetry). Hypotonia, developmental coordination disorders, behavioral problems (such as anxiety, ADHD and oppositional disorders) and various congenital anomalies, such as heart defects, diaphragmatic hernia, renal malformations and cryptorchidism, are frequently presented. Neurological abnormalities (visible on MRI) have been reported.


7q31 microdeletion syndrome is a rare chromosomal anomaly characterized by speech and language disorder, predominantly presenting as an apraxia of speech, sometimes associated with oral motor dyspraxia, dysarthria, receptive and expressive language disorder, and hearing loss. Individuals with larger deletions in this region have also been reported to display intellectual disability and autism.


8p inverted duplication/deletion syndrome

A rare chromosomal anomaly clinically characterized by mild to severe intellectual disability, severe developmental delay (psychomotor and speech development), hypotonia with tendency to later develop progressive hypertonia, and characteristic facial features. The main congenital anomalies associated include central nervous system (CNS) malformations such as hypoplasia/agenesis of the corpus callosum (80%), skeletal abnormalities such as scoliosis/kyphosis or dislocated hips (60%), and congenital heart defects (25%).

Summary:
Epidemiology
About 60 patients have been reported. Whilst epidemiological data is limited, the prevalence at birth has been estimated between 1/10,000-30,000 in Europe.
Clinical description
The most common clinical manifestations include developmental delay, mild to severe degree of cognitive deficit, lack or delay of expressive speech and language and hypotonia, contributing to a mild-severe global developmental delay. Most children with invdupdel(8p) have been reported to be happy natured, sociable and communicative albeit non-verbal, but some may exhibit attention deficits, impulsivity and hyperactivity. In this view, it has been also estimated that between thirty to fifty percent of individuals with invdupdel(8p) may develop a neurodevelopmental disorder during infancy. Facial dysmorphism, more noticeable in childhood, is subtle and frequently includes a prominent forehead, temporal baldness, anteverted nostrils, eversion of the lower lip, large mouth and ears and a short neck. Adults with invdupdel(8p) have height ranging from normal to exceptionally tall, and have a tendency to develop progressive hypertonia, spastic quadriplegia and orthopedic conditions like contracted joints and scoliosis. Albeit, a wide range of congenital malformations (such as cardiac defects, eye and urinary system anomalies) and other skeletal abnormalities have also been reported, the most common congenital malformation being corpus callosum hypoplasia/agenesis.
Etiology
The invdupdel(8p) consists of a deletion distal to the 8p23 region followed by an intermediate intact segment, and a proximal inverted duplication of various extensions. These rearrangements are mediated mainly by two olfactory receptor gene clusters or defensin repeat (ORDRs) at the breakpoints; the polymorphic 8p23 inversion between these clusters increases the susceptibility on 8p to rearrangements. Thus, the inverted duplication with a terminal deletion of the short arm of chromosome 8 mostly occurs as either an inverted duplication from centromere to D8S552 with a pter deletion from D8S349 or as an inverted duplication from 8p11.2 or 8p21 to D8S552, with a telomeric deletion from D8349. To date, all invdupdel(8p) occurred de novo, but the inversion allele is frequently found in one of the parents, and has an estimated allele frequency of 27% in the general Japanese population.
Diagnostic methods
Diagnosis is based on clinical manifestations and agenesis of the corpus callosum on brain magnetic resonance imaging (MRI) leading to chromosomal analysis. Molecular techniques (FISH, MLPA, CGH array) can be used for the genetic characterization of the above-mentioned rearrangements.
Differential diagnosis
Differential diagnosis includes other multiple congenital anomalies/intellectual deficit syndromes such as Trisomy 8p, in particular those carrying an 8p21-p22 duplication.
Antenatal diagnosis
Antenatal diagnosis is based on ultrasound detection of fetal abnormalities (e.g. agenesis of corpus callosum) and cytogenetic analysis after amniocenteses or chorionic villus sampling.
Genetic counseling
Genetic counseling is recommended. Invdupdel(8p) rearrangements occur de novo; however, parents can carry a harmless common inversion involving the 8p23.1 segment (prevalence 1/4 to 1/5) which on rare occasions might lead to the more complex invdupdel(8p) rearrangement in their offspring.
Management and treatment
Physiotherapy from an early age as well as occupational therapy and speech therapy are recommended. Some patients benefit from music therapy. No gross orthopedic complications are noted. However, regular follow-up is needed.
Prognosis
There is no report on life expectancy. The majority of invdupdel(8p) individuals will need lifelong, full-time care. Spastic quadriplegia may be slowly progressive with age.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Andrea BARTULI | ITHACA* - Dr Marina MACCHIAIOLO | ITHACA* - Dr Davide VECCHIO | ITHACA*

                                * European Reference Network


8p11.2 deletion syndrome is a contiguous gene syndrome characterized by the association of congenital spherocytosis, dysmorphic features, growth delay and hypogonadotropic hypogonadism.

Summary:
Epidemiology
It has been described in 8 patients to date.
Clinical description
Common dysmorphic features include micrognathia, microcephaly, preauricular pits, high-arched palate and abnormal ears. All patients except one have intellectual deficit. In one patient, the association of anosmia was suggestive of Kallmann syndrome (see this term).
Etiology
The syndrome is caused by deletions of the proximal part of the short arm of chromosome 8 (8p11.1 to 8p21). The deletions can be cytogenetically detected and their size is variable. The loss of the ankyrin-1 gene (ANK1) results in congenital spherocytosis.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


8p23.1 duplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 8, with a highly variable phenotype, principally characterized by mild to moderate developmental delay, intellectual disability, mild facial dysmorphism (incl. prominent forehead, arched eyebrows, broad nasal bridge, upturned nares, cleft lip and/or palate) and congenital cardiac anomalies (e.g., atrioventricular septal defect). Other reported features include macrocephaly, behavioral abnormalities (e.g., attention deficit disorder), seizures, hypotonia and ocular and digital anomalies (poly/syndactyly).


8p23.1 deletion involves a partial deletion of the short arm of chromosome 8 characterized by low birth weight, postnatal growth deficiency, mild intellectual deficit, hyperactivity, craniofacial abnormalities, and congenital heart defects.

Summary:
Epidemiology
The prevalence is unknown but 8p23.1 deletions are rare. To date, over 50 cases of interstitial or terminal 8p23.1 have been reported without a notable gender discrepancy.
Clinical description
The clinical manifestations are variable and do not depend on the size of the deletion, since this is the same in the majority of patients. Most common manifestations include prenatal and postnatal growth retardation, low birth weight, mild to moderate intellectual deficit, psychomotor retardation, poor speech, seizures, behavioral problems such as hyperactivity and impulsiveness. Frequent craniofacial abnormalities include microcephaly, high and narrow forehead, broad nasal bridge, epicanthic folds, high arched palate, short neck and low set unusually shaped ears. Furthermore congenital heart defects (atrioventricular, septal defects, pulmonary stenosis), congenital diaphragmatic hernia and in boys cryptorchidism and hypospadias have been frequently reported. Some affected individuals have been reported to have normal intelligence.
Etiology
The 8p23.1 deletion is likely to arise through non-allelic homologous recombination mediated by flanking low-copy repeats (LCRs), explaing the common size of approximately 3.4 Mb. The congenital heart defects and diaphragmatic hernia are most likely explained by haploinsufficiency for GATA4.
Diagnostic methods
Diagnosis is based on clinical manifestations leading to chromosomal analysis. 8p23.1 deletions are often missed by standard karyotyping, and mostly detected by molecular karyotyping. Molecular techniques may be used for the genetic characterization of the deletion (FISH, MLPA, aCGH).
Differential diagnosis
Differential diagnosis includes monosomy 22q11 (velocardiofacial syndrome; see this term). Accurate chromosomal analysis confirms the differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis is possible by amniocentesis or chorionic villus sampling and molecular cytogenetic analysis.
Genetic counseling
Genetic counseling is recommended. Most 8p23.1 deletions occur de novo. However, parents can carry and transmit the chromosomal rearrangement to their children as well, with a risk of 50% for each child.
Management and treatment
Management involves assessment, treatment and a regular follow-up by appropriate specialists, including a general practitioner, pediatrician and cardiologists. Early diagnosis and access to major developmental therapies aiming at obtaining the best developmental outcome have been proven beneficial.
Prognosis
Life expectancy is considered normal provided that there is no major congenital heart anomaly or a diaphragmatic hernia.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Pr Koenraad DEVRIENDT


The newly described 8q12 microduplication syndrome is associated with unusual and characteristic multi-organ clinical features, which include hearing loss, congenital heart defects, intellectual disability, hypotonia in infancy, and Duane anomaly (see this term).

Summary:
Epidemiology
It has been described in two patients.
Clinical description
The mild facial dysmorphism is characterized by high, arched eyebrows and unilateral narrowing of the palpebral fissure and retraction of the globe caused by Duane anomaly (Duane anomaly is a form of complex strabismus characterized by limited ocular abduction and variably limited adduction accompanied by retraction of the globe, which narrows the palpebral fissure).
Etiology
This microduplication was identified by microarray-based comparative genomic hybridization (aCGH). The lack of recurrent breakpoints in these two cases and the absence of any low-copy repeats (LCR) pairs that flank these de novo events do not support non-allelic homologous recombination as the mutation mechanism. The 8q12 region includes CHD7 and it is proposed that this gene, associated with CHARGE syndrome by haploinsufficiency, causes a different phenotype by gain-of-dosage.

                            Last update:
                            May 2010

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ