A rare, genetic pituitary disease characterized by infantile-onset, rapid and excessive acceleration of linear growth and body size due to mixed growth hormone (GH)- and prolactin-secreting adenomas and/or pituitary hyperplasia. Patients present with gigantism and may have associated acromegalic features (e.g. coarse facial features, frontal bossing, prognathism, increased interdental space) as well as marked enlargement of hands and feet, soft tissue swelling, increased appetite and acanthosis nigricans.

Summary:
Epidemiology
To date, less than 40 cases have been described worldwide. It accounts for 10% of cases of pituitary gigantism with a known genetic cause.
Clinical description
The onset of disease is in early infancy and may even be present as early as the neonatal period. Pituitary adenoma and/or hyperplasia leads to hypersecretion of GH and insulin-like growth factor 1 (IGF-1). Prolactin secretion is elevated in almost all cases and approximately one third of patients have elevated circulating levels of hypothalamic growth hormone releasing hormone (GHRH). Elevated GH and IGF-1 lead to increased growth in infants, that is usually apparent in the first 12 months of life, and a diagnosis is made usually by the age of 3 years. Increased height and weight are associated with marked increases in hand and foot sizes. Pituitary adenomas are usually macroadenomas (>10 mm diameter) at diagnosis. Height increases in affected children can be very marked in comparison with their peers (Z scores >+5 to +8.7 SDS).
Etiology
The disorder is caused by a GH and prolactin secreting pituitary adenoma and/hyperplasia. Patients with X-linked acrogigantism have a duplication on chromosome Xq26.3 that includes the gene GPR101, which is highly overexpressed in pituitary adenoma tissue.
Diagnostic methods
Diagnostic methods include array comparative genomic hybridization (aCGH) and digital droplet PCR as genetic tests.
Differential diagnosis
In early childhood pituitary gigantism due to a growth hormone secreting pituitary adenoma can be associated with other conditions like AIP germline mutations, McCune-Albright syndrome, and rarely MEN1 syndrome, or Carney complex. For familial X-LAG, the main differential diagnosis is familial isolated pituitary adenomas (FIPA).
Antenatal diagnosis
Prenatal diagnosis is possible.
Genetic counseling
The condition is X-linked dominant; however most cases occur sporadically. X-linked mother-to-son transmission has been reported in three cases; no cases of paternal transmission has been identified to date. Where there is vertical transmission, the Xq26.3 duplication occurs constitutively in the germline; in contrast, sporadic male cases exhibit somatic mosaicism. Genetic counseling should be proposed to individuals having the germline disease-causing Xq26.3 duplication informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
The disorder usually requires a multimodal therapeutic approach combining surgery, medical therapy and rarely radiotherapy. As the anterior pituitary can be extensively affected by adenoma and hyperplasia, early effective treatment to lower growth hormone and IGF-1 to normal levels can be challenging. In many cases, radical neurosurgery is required to widely resect affected anterior pituitary tissue. Residual tumor tissue can lead to long-term growth hormone and IGF-1 over-secretion and continued overgrowth; medical therapy with a growth hormone antagonist (pegvisomant) is usually effective. In X-linked acrogigantism, hormonal control with a somatostatin analog therapy is usually unsuccessful. Control of elevated prolactin levels can be achieved using a low-dose dopamine agonist. Hypopituitarism, involving multiple hormonal axes, and diabetes insipidus are possible post-surgical complications.
Prognosis
Without effective intervention, pituitary gigantism worsens in severity and expansion of the pituitary adenoma continues. Early diagnosis and effective treatment in X-linked acrogigantism can lead to normal adult height. Unmanaged hypopituitarism may lead to morbidity.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Albert BECKERS  - Dr Adrian DALY


A rare genetic adrenal disease characterized by primary adrenal insufficiency (AI) and/or hypogonadotropic hypogonadism (HH). Male patients typically present with AI with acute onset in infancy or insidious onset in childhood. Clinical features of AI include hyperpigmentation, vomiting, poor feeding, failure to thrive, seizures, vascular collapse, and sometimes sudden death. HH manifests later as delayed or arrested puberty. In rare cases, patients become symptomatic in early adulthood with delayed-onset AI, partial HH, and/or infertility. Histologically, the adrenal glands lack the permanent adult cortical zone. The remaining cells are larger than fetal adrenal cells (''cytomegalic'') and contain characteristic nuclear inclusions.


A rare progressive peroxisomal disorder characterized by endocrine dysfunction (adrenal failure and sometimes testicular insufficiency), progressive myelopathy, peripheral neuropathy and, variably, progressive leukodystrophy.

Summary:
Epidemiology
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder with an estimated birth prevalence of 1/17,000 (male and female). It has been reported throughout the world.
Clinical description
X-ALD affects males and females, although symptoms and disease progression differ. The age of onset is highly variable and the rate of progression is unpredictable. Male patients usually present in childhood with signs and symptoms of adrenal failure (80% of male patients develop adrenal failure before the age of 18) or with a rapidly progressive leukodystrophy (40% of male patients before the age of 18, with a lifetime prevalence of 60%). Leukodystrophy is initially clinically silent, but eventually neuropsychiatric symptoms develop, followed by focal deficits like hemiparesis and auditory agnosia, and occasionally epileptic seizures. In early adulthood male patients develop a progressive myelopathy (and peripheral neuropathy) with a gait disorder and incontinence. Progression is slow (over years). Penetrance of this myelopathy is complete, although age of onset and progression are highly variable (some patients require a walking aid whilst others remain ambulatory). Female patients virtually never develop adrenal failure or leukodystrophy. About 90% develop a myelopathy and peripheral neuropathy, but at a later age (after 40 years of age) and with slower progression (over decades) than in males.
Etiology
X-ALD is caused by variants of ABCD1 (Xq28), with about 900 different mutations reported. There is no geno-phenotype correlation. The encoded protein peroxisomal transmembrane protein is involved in the transport of very long-chain fatty acid CoA-esters (VLCFA) from the cytosol into the peroxisome. Although the exact pathophysiology is poorly understood, perturbed VLCFA homeostasis in glial cells may contribute to the destabilization of the myelin sheath and impairment of axonal function.
Diagnostic methods
If there is clinical suspicion, the diagnosis is established by determining plasma VLCFA (C26:0 and C26:0/C22:0 ratio) which is increased in all male patients; up to 15% of female patients have normal VLCFA. Recently, C26:0-lysophosphatidylcholine in bloodspots or plasma has been validated as diagnostic marker, and is elevated in all male and virtually all female patients. The diagnosis can be confirmed by ABCD1 mutation analysis. If necessary, functional assays in cultured skin fibroblasts are available. In case of leukodystrophy, the MRI pattern is virtually pathognomonic. Adrenal failure can be established with an ACTH stimulation test. Newborn screening for X-ALD has been recently implemented in certain regions.
Differential diagnosis
Testing for X-ALD is recommended in all males presenting with adrenal failure (especially in cases of isolated glucocorticoid deficiency). In adult men or women presenting with a chronic myelopathy, the differential diagnosis is large and includes both acquired and genetic disorders. There is no relevant differential diagnosis for presentation with leukodystrophy.
Antenatal diagnosis
In case of a positive family history and a fetus at risk, genetic prenatal diagnosis is possible.
Genetic counseling
The disorder is X-linked. Male patients transmit the disorder to all of their daughters, but never to a son. Female patients transmit the disorder to 50% of their sons and daughters. In case a patient is diagnosed, family screening and counseling is recommended.
Management and treatment
Adrenal insufficiency in X-ALD is treated by hydrocortisone (and if needed fludrocortisone) by an endocrinologist. For the progressive myelopathy there is currently no disease modifying treatment available. The leukodystrophy is treatable with allogeneic hematopoietic cell transplant (HCT), although the outcome is only acceptable when treated in the early stages (Loes score < 9). Autologous HCT after ex vivo lentiviral gene therapy is pending approval in the U.S.A and Europe.
Prognosis
Pre-symptomatic diagnosis permits monitoring for the occurrence of adrenal failure and the onset of cerebral ALD. If appropriate treatment is initiated, severe morbidity and mortality can be prevented. There is currently no treatment to prevent the occurrence or progression of the myelopathy. However, with appropriate supportive care life expectancy is near normal.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Dr M. [Marc] ENGELEN | ERN-RND*

                                * European Reference Network


A clinically variable form of isolated agammaglobulinemia, an inherited immunodeficiency disorder, characterized in affected males by recurrent bacterial infections during infancy.

Summary:
Epidemiology
Estimated prevalence is 1/350,000 to 1/700,000. Annual incidence is not known. The disorder has been reported in various ethnic groups worldwide. Only males are affected and females are asymptomatic carriers.
Clinical description
Affected individuals are usually healthy in the first few months of life due to residual maternal immunoglobulins. The majority of patients develop recurrent or persistent bacterial infections, most commonly caused by S. pneumoniae and H. influenzae, within the first two years of life,: otitis media, conjunctivitis, sinusitis, respiratory infections, diarrhea and skin infections (impetigo, cellulitis, abscesses, and furuncles). Other severe infections may include empyema, meningitis, sepsis, or septic arthritis. Pyoderma or cellulitis (associated with neutropenia) and pseudomonas or staphylococcal sepsis are frequent presenting findings, particularly in patients less than 12 months of age. Lymph nodes, tonsils, and other lymphoid tissues are unusually small or absent. Rare patients are reported to have vitiligo, erythematous rash, or alopecia totalis. Infections tend to persist throughout adulthood. Affected patients are reported to have a higher susceptibility to severe and chronic enteroviral infections. Growth and development are usually normal. Some patients have a less severe clinical presentation and are not recognized as immunodeficient until 10 years of age or later. Complications of X-linked agammaglobulinemia (XLA) include progressive lung disease, chronic sinusitis, inflammatory bowel disease, arthritis , as well as neurological changes.
Etiology
XLA is caused by mutations in the BTK gene (Xq21.33-q22) involved in B lymphocyte differentiation and maturation.
Diagnostic methods
A diagnosis of XLA should be considered in patients with recurrent or persistent otitis media, pneumonia, sinusitis, and conjunctivitis starting before age five years or severe bacterial infections such as sepsis, meningitis, cellulitis, or empyema. A family history consistent with X-linked transmission also points to this diagnosis. Suspicion can be confirmed with blood tests showing low serum Ig and markedly reduced B lymphocyte counts. Molecular genetic testing can also be used to establish or confirm the diagnosis.
Differential diagnosis
Differential diagnoses include autosomal recessive or dominant agammaglobulinemia, common variable immunodeficiency (CVID), hyper IgM syndrome and severe combined immunodeficiency (SCID) (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible following identification of the disease-causing mutation in the family.
Genetic counseling
XLA, as the name indicates, follows an X-linked pattern of inheritance. Nearly 50% of cases are familial, while the remainder are thought to be related to de novo mutations. Genetic counseling should be provided to members of affected families.
Management and treatment
There is no curative treatment for XLA but good disease control can be achieved through consistent gammaglobulin therapy. This can be given intravenously (400-600 mg/kg every 3 to 4 weeks) or subcutaneously (100 mg/kg every week). Therapy should be started as early as possible. Some immunologists advocate chronic prophylactic antibiotics and treatment of acute infections should be prolonged and at maximal doses of antibiotics.
Prognosis
Most patients with XLA lead a normal life. Life expectancy may be reduced in some patients as a result of complications such as severe infections and chronic pulmonary damage. Early therapeutic measures and treatment compliance are major prognostic factors.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Dr Marie Ellen CONLEY


X-linked alpha-thalassemia-intellectual disability syndrome

A rare X-linked syndromic intellectual disability characterized by profound developmental delay, facial dysmorphism, genital abnormalities and alpha thalassemia.

Summary:
Epidemiology
More than 200 patients with X-linked alpha thalassemia intellectual disability (ATR-X) syndrome have been reported. Whilst data is limited worldwide, in Japan the prevalence at birth is estimated at 1/60,000-80,000. Males are predominantly affected.
Clinical description
Affected neonates may present with hypotonia and feeding difficulties. The distinctive facial appearance is most readily recognized in early childhood. Facial hypotonia is associated with upswept frontal hair, widely spaced eyes with epicanthic folds, a depressed nasal bridge and a small triangular upturned nose. The upper lip is tented and the lower lip full and everted. The frontal incisors are widely spaced and there is prodigious drooling. Language is usually very limited. Motor milestones may be delayed and some children never walk. Seizures occur in about one third of the cases. While many patients are affectionate with their caregivers, some exhibit autistic-like behavior. Genital abnormalities are observed in 80% of children and range from undescended testes to ambiguous genitalia. Microcephaly and short stature are common. Alpha thalassemia is not always present. Female carriers are usually physically and intellectually normal.
Etiology
This syndrome is X-linked recessive and results from mutations in the ATRX gene (Xq21.1). This gene encodes the widely expressed ATRX protein. ATRX mutations cause diverse changes in the epigenetic landscape throughout the genome including the pattern of DNA methylation. These are associated with changes in gene expression which are thought to contribute to the clinical phenotype.
Diagnostic methods
The diagnosis can be established by detection of alpha thalassemia, identification of ATRX gene mutations, characteristic changes in DNA methylation, ATRX protein studies in affected males and X-inactivation studies in carrier females.
Differential diagnosis
There is phenotypic overlap with Coffin-Lowry syndrome, Angelman syndrome, Smith-Lemli-Opitz syndrome and Pitt-Hopkins syndrome. There are readily available diagnostic tests for these disorders.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is an X-linked recessive condition. With the exception of two reported heterozygous females with intellectual disability, female carriers are phenotypically and intellectually normal. Genetic counseling should be offered to mothers and female relatives of affected individuals. For a female who has been identified as a carrier, there is a 50% risk of passing on the disease allele with each pregnancy but, since only males are clinically affected, the risk of having an affected child is 25% for each pregnancy.
Management and treatment
Management is multidisciplinary. Young children must be carefully monitored for gastro-esophageal reflux as it may cause death through aspiration. Episodes of unexplained persistent distress may have a gastrointestinal cause with volvulus a known cause. Drooling is frequently seen but, because of reduced gastrointestinal motility, anticholinergics should be used with caution. Constipation is common and initial treatment should be standard. The possibility of cryptorchidism should be assessed in all children. Intra-abdominal testes, which are usually dysgenic, should be removed because of the long-term risk of malignancy. Abnormalities of the renal/urinary system are common, can lead to urinary tract infections, and should be investigated at diagnosis. Alpha thalassemia may be present and give rise to a mild hypochromic, microcytic anemia; this does not require treatment. Iron is not indicated unless the iron stores are low. Asplenia is rare, but if confirmed, antibody prophylaxis and vaccination to prevent pneumococcal and menigococcal infections is recommended. Osteosarcoma has been observed in a small number of affected individuals; painful lesions of the bones should be investigated to exclude osteosarcoma.
Prognosis
A number of individuals with ATR-X are fit and well in their 30s and 40s.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Pr Richard GIBBONS


A rare renal disease characterized by the association of X-linked Alport syndrome (glomerular nephropathy, sensorineural deafness and ocular anomalies) and benign proliferation of visceral smooth muscle cells along the gastrointestinal, respiratory, and female genital tracts and clinically manifests with dysphagia, dyspnea, cough, stridor, postprandial vomiting, retrosternal or epigastric pain, recurrent pneumonia, and clitoral hypertrophy in females.

Summary:
Epidemiology
Prevalence of X-linked Alport syndrome-diffuse leiomyomatosis (XLAS-DL) is unknown. It affects both males and females.
Clinical description
Symptoms of glomerular disease (hematuria, progressive proteinuria and renal impairment) typically appear late in childhood, and in males is more severe with faster progression. Patients also have sensorineural deafness and ocular anomalies (anterior lenticonus, congenital cataracts, corneal opacities, maculopathy, fleck retinopathy and temporal retinal thinning). Diffuse leiomyomatosis is severe in males and in females, and typically involves the esophagus, causing dysphagia, postprandial vomiting and retrosternal or epigastric pain. Tracheobronchial lesions lead to dyspnea, cough, stridor and recurrent pneumonia due to aspiration. Affected females show clitoral hypertrophy and variable involvement of labia majora and uterus. Perirectal or perineal leiomyomas are uncommon and associated with constipation.
Etiology
XLAS-DL is due to contiguous gene deletions encompassing the 5' ends of COL4A5 (Xq22.3) and COL4A6 (Xq22.3) genes, which respectively encode the alpha-5 and alpha-6 chain of type IV collagen. COL4A5 is an integral component of the type IV collagen 3,4,5 network, a key component of the glomerular basement membrane (GBM), and COL4A6 is a component of the type IV collagen 5,5,6 network present in Bowman's capsule but not in the healthy GBM.
Diagnostic methods
X-linked Alport syndrome is suspected on clinical presentation and family history of hematuria, deafness and/or renal impairment, and is confirmed by genetic analysis of COL4 genes. Histological evaluation of the kidney is valuable in case of equivocal or unavailable genetic testing. Immunohistochemical assays can also be performed on kidney and skin specimens, and electron microscopy provides ultrastructural analysis of basement membranes. An abnormal expression pattern of type IV collagen chains confirms the diagnosis; however, a normal expression does not eliminate diagnosis. The diagnosis of leiomyomatosis requires a biopsy of the affected tissue. Radiological imaging can identify lesions and the associated deformation of the affected tract.
Differential diagnosis
The differential diagnosis regarding the combination of glomerular disease with deafness includes Fechtner syndrome, MYH9-related disease, MELAS and May-Hegglin thrombocytopenia. The main differential diagnosis for glomerular hematuria is IgA nephropathy, familial benign hematuria and membranoproliferative glomerulonephritis. Leiomyomata can occur as sporadic benign smooth muscle tumors, without AS.
Antenatal diagnosis
Prenatal testing for at risk pregnancies is possible where the COL4A5-COL4A6 deletion has been previously identified in a family member, and if a molecular diagnosis of the inherited deletion can be reliably performed.
Genetic counseling
XLAS-DL is transmitted as X-linked dominant trait and, thus, heterozygous females will also express the disease. Genetic counseling for affected families is recommended.
Management and treatment
Regular monitoring of blood pressure and urinalysis are important to identify hypertension or microalbuminuria/proteinuria and treat accordingly with angiotensin converting enzyme inhibitors/angiotensin receptor blockers. This additionally permits timely clinical management of chronic kidney disease, including eventual renal replacement therapy with either preemptive transplantation or dialysis. Surgical intervention is required for symptomatic leiomyomas. Ocular manifestations rarely need intervention but an ophthalmologist is helpful for diagnosis since ocular involvement is often asymptomatic. Audiological evaluation should be performed regularly and hearing aids should be prescribed when appropriate.
Prognosis
The prognosis of AS is poor due to the progression to ESRD (often affecting young adults). Renal transplantation is successful in individuals with AS, since development of anti-glomerular basement membrane antibodies is a rare event.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Laurence HEIDET | ERKNet* - Pr Rachel LENNON | ERKNet*

                                * European Reference Network


A rare, genetic, primary bone dysplasia with increased bone density disorder characterized by benign, isolated, calvarial thickening, presenting with prominent frontoparietal bones, a high forehead with ridging of the metopic and sagittal sutures, lateral frontal prominences, and facial dysmorphism comprising a flat nasal root and short, upturned nose. Increased intracranial pressure and cranial nerve entrapment are not associated. There have been no further descriptions in the literature since 1986.


X-linked central congenital hypothyroidism with late-onset testicular enlargement is a rare, genetic, endocrine disease characterized by central hypothyroidism, testis enlargement in adolescence resulting in adult macroorchidism, delayed pubertal testosterone rise with a subsequent delayed pubertal growth spurt, small thyroid gland, and variable prolactin and growth hormone deficiency.


A rare X-linked congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and that presents at birth with marked weakness, hypotonia and respiratory failure.

Summary:
Epidemiology
The birth prevalence of X-linked centronuclear myopathy (XLMTM) is estimated at 1/50,000 males.
Clinical description
The disease is characterized by a severe phenotype in males presenting at birth with marked weakness, hypotonia and respiratory failure. Signs of antenatal onset are frequent and comprise reduced fetal movements and polyhydramnios. Thinning of the ribs is observed on chest radiographs of the newborn. Birth asphyxia may be the presenting feature. A family history of either male neonatal deaths or miscarriages is common. Affected infants are often macrosomic, with a body length above the 90th centile and large head circumference. External ophthalmoplegia is commonly associated. Testes are frequently undescended. Pyloric stenosis and cavernous hemangiomas of the liver have been reported in some long-term survivors.
Etiology
XLMTM is caused by mutations in the myotubularin (MTM1); Xq27.3-q28) gene.
Diagnostic methods
Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features. Genetic testing confirms the diagnosis.
Differential diagnosis
The main differential diagnoses include congenital myotonic dystrophy and other conditions characterized by severe neonatal hypotonia.
Antenatal diagnosis
Prenatal diagnosis is possible where the mutation has been previously identified in a family member.
Genetic counseling
The pattern of inheritance is x-linked recessive. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%; female offspring have a 50% risk of being carriers. The degree of disease penetrance depends on skewed X-inactivation; the majority of female disease carriers are asymptomatic but may show signs of only mild muscle weakness or urinary incontinence, indicating smooth muscle involvement. Genetic counseling should be offered to all patients and families.
Management and treatment
There is currently no curative treatment available. Management is supportive and based on a multidisciplinary approach.
Prognosis
In the majority of cases, the course is fatal within the first months of life. A proportion of affected males may survive into their teens or beyond. In these cases, the survival depends on a substantial degree of medical intervention and often constant ventilation.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI


A progressive peroxisomal disease, characterized by endocrine dysfunction (adrenal failure and sometimes testicular insufficiency), progressive myelopathy and peripheral neuropathy, and leukodystrophy. Age of onset is highly variable, but often in the first decade.


X-linked cerebral-cerebellar-coloboma syndrome is a rare, genetic syndrome with a cerebellar malformation as major feature characterized by cerebellar vermis hypo- or aplasia, ventriculomegaly, agenesis of corpus callosum and abnormalities of the brainstem and cerebral cortex in association with ocular coloboma. Clinically, patients show hydrocephalus at birth, neonatal hypotonia with abnormal breathing pattern, ocular abnormalities with impaired vision, severe psychomotor delay, and seizures.


X-linked Charcot-Marie-Tooth disease type 1

A rare genetic peripheral sensorimotor neuropathy characterized by an X-linked dominant inheritance pattern and adolescence onset in males of progressive, distal, moderate to severe muscle weakness and atrophy in lower extremities and intrinsic hand muscles, pes cavus, bilateral foot drop, reduced or absent tendon reflexes, as well as mild to moderate sensory impairment in lower extremities. Females tend to have milder manifestations or may be asymptomatic. Sensorineural deafness and (often transient) central nervous system involvement have also been reported.


X-linked Charcot-Marie-Tooth disease type 2

A rare genetic peripheral sensorimotor neuropathy characterized by an X-linked recessive inheritance pattern and the infantile-to childhood-onset of progressive, distal muscle weakness and atrophy (more prominent in the lower extremities than in the upper extremities), pes cavus, and absent tendon reflexes. Sensory impairment and intellectual disability has been reported in some individuals.


X-linked Charcot-Marie-Tooth disease type 3

A rare genetic peripheral sensorimotor neuropathy characterized by an X-linked recessive inheritance pattern and the childhood onset of progressive, distal muscle weakness and atrophy (beginning in the lower extremities and then affecting the upper extremities), as well as distal, pansensory loss in the upper and lower extremities, pes cavus, and absent or reduced distal tendon reflexes. Pain and paresthesia are frequently the initial sensory symptoms.


X-linked Charcot-Marie-Tooth disease type 4

A rare genetic, axonal, peripheral sensorimotor neuropathy, characterized by an X-linked recessive inheritance pattern and the neonatal- to early childhood-onset of severe, slowly progressive, distal muscle weakness and atrophy (in particular of the peroneal group), as well as sensory impairment (with the lower extremities being more affected than the upper extremities), pes cavus, areflexia and hammertoes. Sensorineural hearing loss and cognitive impairment may also be associated. Females are asymptomatic and do not display the phenotype.


X-linked Charcot-Marie-Tooth disease type 5

A rare genetic peripheral sensorimotor neuropathy characterized by infancy-to childhood onset of progressive distal muscle weakness and atrophy (first appearing and more prominent in the lower extremities than the upper) which usually manifests with foot drop and gait disturbance, bilateral, profound, prelingual sensorineural hearing loss and progressive optic neuropathy.


X-linked Charcot-Marie-Tooth disease type 6

A rare genetic peripheral sensorimotor neuropathy characterized by principally axonal, peripheral sensorimotor neuropathy with an X-linked dominant inheritance pattern and the childhood-adolescence-onset of slowly progressive, moderate to severe, distal muscle weakness and atrophy of the lower extremities, as well as distal, panmodal sensory abnormalities, bilateral foot deformities (pes cavus, clawed toes), absent ankle reflexes and gait abnormalities (steppage gait). Females are usually asymptomatic or only present mild manifestations (mild postural hand tremor, mild wasting of hand intrinsic muscles).


A disorder that belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases.

Summary:
Clinical description
CMTX1 is characterized by a slowly progressive course: muscle wasting and weakness of distal limb muscles mainly involving the feet, legs and hands (particularly the thenar eminence), with proximal muscle weakness occurring in severe cases; distal sensory loss; loss of deep tendon reflexes; pes cavus and more rarely scoliosis. Rare instances of transient central nervous system (CNS) dysfunction have been described, with dysarthria, dysphagia, weakness, ataxia, and even aphasia and somnolence. All forms of CMTX are rare and are characterized by intellectual deficit (CMTX2, CMTX4), spastic paraplegia (CMTX3), hearing loss (CMTX4, CMTX5, rarely CMTX1), and optic atrophy (CMTX5).
Etiology
CMTX1 is associated with mutations in the GJB1 gene (Xq13.1), encoding connexin 32 (Cx32). Cx32 forms gap-junctions in non-compact myelin produced by myelinating Schwann cells. Cx32 is also expressed in oligodendrocytes, explaining the potential CNS involvement. CMTX5 is associated with mutations in the phosphoribosylpyrophosphate synthetase 1 gene (PRPS1). CMTX1 is transmitted as an X-linked dominant trait and males are more severely affected than females, whereas the other CMTX types are X-linked recessive and female carriers are usually unaffected.
Diagnostic methods
Diagnosis is based on family and personal history, clinical examination, nerve conduction studies (NCS), and DNA testing (for CMTX1). NCS show a sensorimotor polyneuropathy with decreased conduction velocities in males (usually in the intermediate range of 30-45 m/s in upper limb motor nerves) and mildly decreased or even normal velocities in females. In contrast with other CMT types, conduction slowing is frequently nonhomogeneous, with temporal dispersion and sometimes conduction blocks, and the median nerve being more severely affected than the ulnar nerve. Nerve biopsy reveals prominent axonal changes, in spite of nerve conduction slowing, with evidence of ultrastructural abnormalities in the paranodal regions. Auditory evoked potentials usually reveal abnormalities of central waves in the brainstem, consistent with frequent subclinical brain involvement in CMTX1.
Differential diagnosis
Differential diagnosis includes other CMT types and acquired dysimmune neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible for CMTX1 when the mutation is known.
Genetic counseling
As an X-linked dominant trait, there is no male-to-male transmission; female carriers are usually mildly affected and have a 50% risk of transmitting the disease to their offspring.
Management and treatment
There is no drug treatment available. Rehabilitation therapy and surgical treatment of skeletal deformities are the only options.
Prognosis
CMTX1 is moderately severe for affected males, who may loose ambulation capacity later in life.

                            Last update:
                            January 2008

                            - Expert reviewer(s):
                            Dr Davide PAREYSON


X-linked cleft palate and ankyloglossia is a rare, genetic developmental defect during embryogenesis syndrome characterized by the association of complete, partial or submucous cleft palate and ankyloglossia. Patients may also present abnormal uvula (e.g. absent, bifid, shortened or laterally deviated), short lingual frenulum and dental anomalies (e.g. buccal crossbite, absent and/or misshapen teeth). Digital abnormalities, such as mild clinodactyly and/or syndactyly, have also been reported.


X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome is a rare syndromic microphthalmia disorder characterized by microphthalmia with coloboma (which may involve the iris, cilary body, choroid, retina and/or optic nerve), microcephaly, short stature and intellectual disability. Other eye abnormalities such as pendular nystagmus, esotropia and ptosis may also be present. Additional associated abnormalities include kyphoscoliosis, anteverted pinnae with minimal convolutions, diastema of the incisors and congenital pes varus.


X-linked complicated corpus callosum dysgenesis

A congenital, X-linked, clinical subtype of L1 syndrome, characterized by variable spastic paraplegia, mild to moderate intellectual disability, and dysplasia, hypoplasia or aplasia of the corpus callosum. In this subtype hydrocephalus, adducted thumbs, or absent speech are not observed.


X-linked complicated spastic paraplegia type 1

A congenital, X-linked, clinical subtype of L1 syndrome, characterized by spastic paraplegia, mild to moderate intellectual disability and normal brain morphology. This subtype represents the milder end of the L1 syndrome spectrum.


X-linked cone dysfunction syndrome with myopia is characterised by moderate to high myopia associated with astigmatism and deuteranopia. Less than 10 families have been described so far. Transmission is X-linked recessive and the locus has been mapped to Xq28.


X-linked congenital generalized hypertrichosis is an extremely rare type of hypertrichosis lanuginosa congenita, a congenital skin disease, which is characterized by hair overgrowth on the entire body in males, and mild and asymmetric hair overgrowth in females. It is associated with a mild facial dysmorphism (anterverted nostrils, moderate prognathism), and, in a kindred, it was also associated with dental anomalies and deafness.


X-linked corneal dermoid (X-CND) is an exceedingly rare, benign, congenital, corneal tumor characterized by bilateral opacification of the cornea with superficial grayish layers and irregular raised whitish plaques, as well as fine blood vessels covering the central cornea, and intact peripheral corneal borders. No other ocular or systemic abnormality is noted. The pattern of inheritance described in the affected family is consistent with X-linked transmission.


X-linked creatine transporter deficiency (CRTR-D) is a creatine deficiency syndrome characterized clinically by global developmental delay/ intellectual disability (DD/ID) with prominent speech/language delay, autistic behavior and seizures.

Summary:
Epidemiology
CRTR-D has been reported in more than 150 individuals worldwide.
Clinical description
The onset of symptoms occurs during infancy, usually before the age of 2 years. Males are mainly affected, but females can also have various combinations and severities of disease manifestations. CRTR-D is consistently characterized by mild to severe intellectual deficit, and expressive speech and language delay. Behavioral disorders (mainly autism and hyperactivity) are present in all affected individuals. Affected individuals often experience seizures and may present low weight gain, muscular hypotonia, and poor muscle mass. Subtle dysmorphic features such as midface hypoplasia, long face, and prominent chin have been reported in various affected male patients. Epilepsy and extrapyramidal symptoms may also occur occasionally. In adult patients, cardiac and gastrointestinal disorders have been reported. Carrier females are typically asymptomatic, but learning disabilities have been described in some.
Etiology
CRTR-D is mostly due to frameshift and splicing mutations in the creatine transporter gene SLC6A8 (Xq28) that result in a cerebral creatine deficiency. An estimated 20% of SLC6A8 mutations can be accredited to de novo mutations, or germinal or somatic mosaicism events.
Diagnostic methods
Diagnosis should be suspected clinically in children with DD/ID plus autistic behavior, as they are considered at risk. Diagnosis is based on the determination of urinary creatine excretion (which is elevated, particularly when measured as urinary creatine to creatinine ratio) and demonstration of creatine deficiency in the brain (as shown by magnetic resonance spectroscopy). These features are less pronounced in females. Diagnosis is confirmed by genetic testing for mutations in the SLC6A8 gene. Creatine uptake studies in cultivated fibroblasts are used to verify the pathogenetic relevance of genetic variants of unclear significance.
Differential diagnosis
Differential diagnosis includes other disorders of creatine deficiency syndrome like guanidinoacetate methyltransferase deficiency and L-arginine:glycine amidinotransferase deficiency (see these terms). In cases with partial cerebral creatine deficiency, argininosuccinic aciduria, citrullinemia type I, and gyrate atrophy of the choroid and retina (see these terms) should be considered.
Antenatal diagnosis
Pre-implantation or prenatal genetic diagnosis for at risk couples is possible if the mutation has been identified in an affected family member.
Genetic counseling
CRTR-D occurs de novo or is inherited in an X-linked manner, with a carrier female having a 50% risk of transmitting the mutation to her offspring. Carrier testing for at-risk relatives in cases of family history is recommended.
Management and treatment
Treatment with high dosages of creatine monohydrate, alone or combined with L-arginine and glycine, has resulted in clinical improvement of seizures and behavior in some patients, but in most cases, it does not appear to increase cerebral creatine. Treatment may also increase muscle mass and improve motor skills, as observed in a small cohort.
Prognosis
CRTR-D is not a life threatening disease; however life expectancy is limited, particularly in those who have severe seizures and associated physical handicaps.

                            Last update:
                            December 2014

                            - Expert reviewer(s):
                            Dr Sylvia STOCKLER


X-linked distal spinal muscular atrophy type 3 is a rare distal hereditary motor neuropathy characterized by slowly progressive atrophy and weakness of distal muscles of hands and feet with normal deep tendon reflexes or absent ankle reflexes and minimal or no sensory loss, sometimes mild proximal weakness in the legs and feet and hand deformities in males.


A rare genodermatosis disease with great phenotypic variation and characterized most commonly by ichthyosis following the lines of Blaschko, chondrodysplasia punctata (CDP), asymmetric shortening of the limbs, cataracts and short stature.

Summary:
Epidemiology
Annual incidence of X-linked dominant chondrodysplasia punctata (CDPX2) has been estimated to be at least 1/400,000 births with 95% of patients being female.
Clinical description
Congenital ichthyosiform erythroderma is the typical neonatal manifestation. Erythema is usually generalized while hyperkeratotic scales generally follow Blaschko's lines and tend to fade during a period of weeks to months. In older children, ichthyosis following Blaschko's lines is the most frequent clinical finding (95% of cases) and it improves with age. Hyperkeratosis, especially involving hair follicles, and late atrophy appear at sites of previous scaling, typically in a follicular pattern (atrophoderma vermiculata). Follicular atrophoderma is particularly common on the trunk, forearms and dorsal aspect of the hands. Patchy areas of cicatricial alopecia are common. Asymmetric shortening of the limbs, usually affecting the humerus and femur, together with CDP, are the most common skeletal abnormalities. Facial dysmorphism (low nasal bridge, frontal bossing, hypertelorism, high arched palate) is common. Joint contractures affecting the hips, hands and feet are frequent. Talus valgus and other deformities may be seen. The vertebral column exhibits moderate to severe scoliosis and short stature is common. Most patients (60%) suffer from cataracts (mainly unilateral), which may be congenital or appear early in life. Microphthalmia, microcornea and epicanthus have been reported. Intelligence is normal.
Etiology
CDPX2 is due to mutations in the EBP gene (Xp11.23-p11.22) encoding the emopamil binding protein (EBP), which acts as a delta8-delta7-sterol isomerase that catalyzes the conversion of 8(9)-cholestenol to lathosterol in the distal cholesterol biosynthesis pathway. A deficiency in EBP leads to the accumulation of 8-dehydrocholesterol (8DHC) and 8(9)-cholestenol in the skin, plasma and other body tissues.
Diagnostic methods
Diagnosis of CDPX2 relies on clinical, biochemical and genetic tests. CDP, usually consisting of epiphyseal stippling, is the fundamental radiological finding. Biochemical analyses show increased levels of 8(9) cholestenol and 8-dehydrocholesterol. Molecular testing for EBP mutations confirms diagnosis.
Differential diagnosis
Differential diagnoses include CDPX1; RCDP; chondrodysplasia punctata, tibia-metacarpal type; CHILD syndrome; systemic lupus erythematosus; MEND syndrome, and vitamin K deficiencies.
Antenatal diagnosis
Prenatal diagnosis and preimplantation genetic diagnosis may be an option for families with a known disease-causing mutation.
Genetic counseling
CDPX2 is inherited in an X-linked dominant manner and genetic counseling is possible. Somatic mosaicism in the father or de novo mutations can explain the occurrence of offspring with CDPX2 when no mutations are found in the mother. Germline mosaicism and anticipation has also been reported in families with CDPX2. In most cases it is lethal in males.
Management and treatment
Management is multidisciplinary. Treatment of skin lesions includes the use of emollients and keratolytics (i.e. ammonium lactate 12%, petrolatum ointment). Topical administration of lovastatin and cholesterol may be beneficial for ichthyosis. Orthopedic management and surgery may be necessary in those with bone deformities. Cataracts should be extracted and vision correction devices provided. Physical, occupational and speech therapies may be necessary. Regular follow-up with dermatologists and ophthalmologists and orthopedic evaluations are recommended. Hearing aids may be needed.
Prognosis
There is usually no effect on life-expectancy (rarely scoliosis can compromise cardiac and pulmonary function) but quality of life may be severely affected.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Rogelio GONZÁLEZ SARMIENTO


X-linked dominant chondrodysplasia, Chassaing-Lacombe type

X-linked dominant chondrodysplasia Chassaing-Lacombe type is a rare genetic bone disorder characterized by chondrodysplasia, intrauterine growth retardation (IUGR), hydrocephaly and facial dysmorphism in the affected males.

Summary:
Epidemiology
Prevalence is unknown. To date, 10 patients (4 males and 6 females) in a single family have been reported through 4 generations.
Clinical description
Three male fetuses were diagnosed prenatally on ultrasonography (skeletal abnormalities and hydrocephaly) leading to termination of the pregnancies. The fourth affected male died at 6 days of life. The disease is severe and probably lethal in males, in whom the clinical picture includes short hands, brachydactyly, hydrocephaly and facial dysmorphism, including frontal bossing, low-set ears, short flat nose and microphthalmia. Other signs may include cerebellar hypoplasia and hyperkeratotic skin. X-rays show severe platyspondyly due to delayed ossification of the vertebrae, thin ribs, moderate shortening of the long bones, hypoplastic iliac wings, poorly ossified pubis, brachydactyly of the fingers and/or toes with cupped metacarpals, metatarsals, and phalanges and hypoplastic square calcaneus. The clinical picture in females is less severe and comprises short stature (128-151 cm), rhizomelic shortening of the limbs, short hands, brachymesophalangia of the 3rd and 4th toes, and may be associated with body asymmetry and mild cognitive impairment.
Etiology
X-linked dominant chondrodysplasia Chassaing-Lacombe type is due to a mutation in the histone deacetylase 6 HDAC6 gene (Xp11.3-q13.1) that causes a nucleotide substitution in the 3' untranslated region (UTR) of the HDAC6 transcript. This mutation lies in the seed sequence of microRNA-433 (hsa-miR-433) and abolishes the post-transcriptional regulation of HDAC6 expression by hsa-miR-433, resulting in the overexpression of the HDAC6 protein.
Genetic counseling
Inheritance is X-linked dominant.

                            Last update:
                            February 2011

                            - Expert reviewer(s):
                            Pr Didier LACOMBE


X-linked dyserythropoietic anemia with abnormal platelets and neutropenia is a rare, genetic, constitutional dyserythropoietic anemia disorder characterized by moderate to severe anemia without thrombocytopenia, variable degrees of neutropenia, and bone marrow biopsy findings of trilineage dysplasia and hypocellularity of erythroid and granulocytic lineages. Peripheral blood findings include anisocytosis, macrocytosis, poikilocytosis, elliptocytes, and fragmented erythrocytes.


X-linked dystonia-parkinsonism (XDP) is a neurodegenerative movement disorder characterized by adult-onset parkinsonism that is frequently accompanied by focal dystonia, which becomes generalized over time, and that has a highly variable clinical course.

Summary:
Epidemiology
Over 500 cases of XDP have been reported in the literature to date, all occurring in the Philippines (Panay Island). The estimated prevalence in the Philippines is 1/322,000 and in the Province of Capiz it is at its highest with a prevalence of 1/4,000 in the male population.
Clinical description
XDP affects mainly males, most female carriers are asymptomatic. The disease typically presents in adulthood (mean: 39 years) with either focal dystonia or, more commonly, parkinsonism. Focal dystonia affects mainly the jaw, neck, eyes and trunk, but also rarely the limbs, pharynx, larynx and tongue, leading to various manifestations such as difficulty with jaw opening and closing, blepharospasm, involuntary tongue protrusion, difficulty swallowing, retrocollis, trunk hyperextension, leg spasms, foot flexion, and foot inversion. Within 2-5 years after onset, 50% of patients have generalized dystonia. Parkinsonism manifests with bradykinesia, rigidity, resting tremor, shuffling gait and postural instability, which may be severe and can lead to walking impairment and frequent stumbling. Less common findings include sensory tricks, myoclonus, chorea and myorhythmia. In those with pure parkinsonism, the disease progresses slowly and is usually non-disabling. Most who develop orobuccolingual and cervical dystonia suffer from lethal complications such as infections, aspiration pneumonia and laryngeal stridor, leading to premature death. Mean duration of illness is 13-16 years.
Etiology
XDP is due to mutations in the TAF1 gene (Xq13.1) encoding the TAF1 RNA polymerase II, TATA box-binding protein-associated factor, 250kDa.
Diagnostic methods
Diagnosis is based on clinical and neuroimaging findings (of postsynaptic striatal and presynaptic nigrostriatal involvement), as well as having a positive family history compatible with X-linked inheritance and maternal Panay Island ancestral roots. MRI usually shows no abnormalities. Molecular genetic testing can confirm the diagnosis by identifying a  TAF1 mutation. Preliminary results from a pilot study indicate olfactory dysfunction in XDP, therefore olfactory testing may also support diagnosis.
Differential diagnosis
Differential diagnoses include Parkinson's disease, hereditary essential tremor, dopa-responsive dystonia and Parkinson-plus syndromes.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known TAF1 mutation.
Genetic counseling
XDP is inherited in an X-linked recessive manner and genetic counseling is recommended. Males with XDP pass the mutation to all of their daughters and none of their sons, whereas female carriers have a 50% risk of passing the mutation to their offspring. Rare de novo mutations have been reported.
Management and treatment
There is no cure for XDP. Treatment involves the use of pharmacological agents and offers only temporary or partial relief. In the early stages of dystonia, benzodiazepines and anticholinergic agents may be effective, especially in combination. Botulinum toxin injections may relieve focal dystonia. Tetrabenazine and zolpidem can improve dystonia once it becomes generalized or multifocal. Those with pure parkinsonism may be responsive to levodopa. Deep brain stimulation has shown promise in a few cases with advanced disease refractory to medication. Periodic swallowing evaluation is recommended, especially in those with dysphagia. Physical therapy may be helpful. Psychological counseling should be offered to patients and their families.
Prognosis
Prognosis is phenotype-dependent. Those with pure parkinsonism have the best prognosis, while those with a combination of parkinsonism followed by the development of orobuccolingual and cervical dystonia, 1-2 years after disease onset, have the worst prognosis, usually becoming bedridden with a reduced life expectancy.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


A rare systemic disease characterized by a severe phenotype in all male patients, combining abnormality of connective tissue typical for Ehlers-Danlos syndrome (including joint hypermobility, scoliosis, soft and doughy skin, hyperextensible skin, abnormal scarring, facial peculiarities, and generalized hypotonia, among others) and eventually lethal congestive heart failure due to polyvalvular disease. Female carriers are affected to a variable degree.


X-linked endothelial corneal dystrophy (XECD) is a rare subtype of posterior corneal dystrophy (see this term) characterized by congenital ground glass corneal clouding or a diffuse corneal haze, and blurred vision in male patients.

Summary:
Epidemiology
Prevalence of this rare corneal dystrophy is unknown. Males are affected more severely than females.
Clinical description
Affected males are born with clouding ranging from a diffuse haze to a ground-glass, milky appearance, which commonly causes blurred vision, and possible nystagmus. Female patients are asymptomatic but have crater-like endothelial abnormalities. The condition is progressive in males and non-progressive in females. In advanced cases, a subepithelial band keratopathy associated with endothelial changes that resemble moon craters is observed.
Etiology
XECD has been mapped to the long arm of the X-chromosome (Xq25) but the causative gene has not been identified.
Diagnostic methods
Light microscopy reveals focal discontinuities and degenerative changes in the corneal endothelial cells which underlie the crater-like changes seen clinically. Descemet membrane is irregularly thickened with small pits and excavations. The corneal epithelium and Bowman zone may be irregularly thinned.
Genetic counseling
Transmission is X-linked recessive.
Management and treatment
A penetrating keratoplasty may be indicated in males if corneal opacification impairs vision significantly. Procedures for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK) are technically difficult in young children.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


X-linked epilepsy-learning disabilities-behavior disorders syndrome is characterized by epilepsy, learning difficulties, macrocephaly, and aggressive behaviour. It has been described in males from a four-generation kindred. It is transmitted as an X-linked recessive trait and is likely to be caused by mutations in the gene encoding synapsin I (Xp11.3-q12).


A rare disorder of heme metabolism characterized by severe cutaneous photosensitivity in affected boys and sometimes in girls, manifesting in childhood.

Summary:
Epidemiology
X-linked erythropoietic protoporphyria (XLPP) has been reported with a prevalence <1/1,000,000.
Clinical description
The disease manifests in infancy or childhood through the onset of severe acute cutaneous photosensitivity in affected boys, with tingling, burning and itching within few minutes of exposure to sunlight or illumination in the visible spectrum (in particular, in the Soret band [400 - 410 nm]), often accompanied by skin edema and redness. Pain may persist for several hours or days after the initial reaction. As protoporphyrin is a lipophilic molecule excreted by the liver, some XLPP patients may develop biliary lithiasis and liver damage. In heterozygous girls, the phenotypes vary from asymptomatic to severe.
Etiology
XLPP is due to gain-of-function mutations in the ALAS2 gene (NM_000032.4) encoding erythrocyte-specific aminolevulinic acid synthase 2.
Diagnostic methods
Diagnosis is based on the presence of high concentrations of protoporphyrin in plasma and red blood cells, and the detection of a plasma fluorescence peak at 635 nm. The percentage of zinc-bound protoporphyrin is reduced but remains higher than in autosomal EPP, and FECH enzyme activity is normal. A liver damage analysis is recommended. Genetic analysis (mutations in the ALAS2 gene) and family screening are also recommended.
Differential diagnosis
Differential diagnosis includes autosomal erythropoietic protoporphyria, phototoxic drug reactions, solar urticaria, contact dermatitis, angioedema, and hydroa vacciniforme.
Antenatal diagnosis
Antenatal diagnosis is theoretically possible, but not offered.
Genetic counseling
The transmission pattern is X-linked dominant.
Management and treatment
Treatment is based on preventive measures similar to those proposed for the treatment of autosomal erythropoietic protoporphyria. Since liver disease is the major risk in XLPP, regular monitoring of liver function is recommended. Sequential liver and bone marrow transplant should be considered in the treatment of severe cases with liver damage.
Prognosis
The prognosis of XLPP depends on the progression of liver disease. However, photosensitivity can affect patients' quality of life. In contrast to EPP, oral iron supplementation in XLPP patients with iron deficiency anemia reduces the concentration of protoporphyrins in the blood and improves symptoms.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome

A rare syndromic genetic deafness characterized by congenital hearing loss, atresia or stenosis of the external auditory canal, dilated internal auditory canal, malformation of the inner ear (incomplete separation of the cochlea basal turn from the fundus of the internal auditory canal), in combination with abnormal auricular shape and facial dysmorphism (including thick eyebrows, ptosis, broad nasal root, and telecanthus). Intelligence is normal and developmental delay is absent.


X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, and dysmorphic facial features (such as facial asymmetry, prominent forehead, short palpebral fissures, low nasal bridge, smooth and long philtrum, thin upper lip, and low-set, posteriorly rotated, dysplastic ears), exclusively affecting females. Additional reported manifestations include short stature, choanal atresia, scoliosis, congenital ocular, dental, cardiac, and urogenital anomalies, as well as hypotonia, seizures, and structural brain abnormalities, among others.


X-linked hereditary sensory and autonomic neuropathy with deafness

A rare peripheral neuropathy characterized by the association of an axonal sensory and autonomic neuropathy with hearing loss.

Summary:
Epidemiology
It has been described in a large five-generation Chinese family.
Clinical description
Onset occurred in the second decade of life (with an average age of onset of 13 years) with mild to severe hearing impairment due degeneration of the auditory nerve (type 1 auditory neuropathy), followed by late-onset of a diffuse and progressive peripheral sensory neuropathy.
Etiology
The causative gene was mapped to the AUNX1 locus on chromosome Xq23-27.3.
Genetic counseling
Transmission was X-linked recessive.

                            Last update:
                            January 2009


A rare hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia, and diminished growth.

Summary:
Epidemiology
It is the most common form of hereditary hypophosphatemia with a prevalence of approximately 1/47,000 worldwide. The disease affects both sexes equally.
Clinical description
X-linked hypophosphatemia (XLH) manifests during childhood with typical clinical features of rickets such as short stature, bone pain, and skeletal deformities (bowed legs, genu varum, rachitic rosary...). Dental abnormalities (recurrent abscesses, abnormal enamel) are observed in children and adults. Cranial anomalies are also observed due to thickness of parietal and frontal bones and craniosynostosis. In adults, musculoskeletal symptoms are the main feature of the disease with a heavy burden on the patient's quality of life. They include fractures and pseudofractures, pain, joint stiffness, osteoarthritis, enthesopathy, and muscle weakness.
Etiology
The disease is caused by various variants in the PHEX gene (Xp22.1) which encodes an endopeptidase expressed predominantly in bone and teeth. Although the mechanism is unknown, the PHEX variants lead to increased circulating levels of FGF-23, a phosphate-regulating hormone. Through its action on sodium-phosphate cotransporter genes in the proximal renal tubule, as well as CYP271B and CYP24A1, increased FGF-23 ultimately results in reduced renal phosphate reabsorption, and decreased intestinal phosphate and calcium absorption, consequently leading to abnormal bone mineralization.
Diagnostic methods
Diagnosis is based on clinical and biochemical findings, and typical rickets/osteomalacia radiographic features. Biochemical findings include elevated circulating levels of FGF-23 associated with hypophosphatemia, hyperphosphaturia, normal serum levels of calcium, increased or normal plasma levels of parathyroid hormone, and increased levels of alkaline phosphatase. Phosphate excretion can be evaluated by measuring the maximum tubular reabsorption per glomerular filtration rate. Molecular genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes autosomal dominant and autosomal recessive hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome, vitamin D deficiency and tumor-induced osteomalacia.
Genetic counseling
XLH is transmitted as an X-linked dominant trait with complete penetrance, but variable expressivity. Genetic counseling should be recommended to affected patients.
Management and treatment
Multidisciplinary care by experts in the field of XLH is recommended. Current conventional treatment consists of active vitamin D analogs and phosphate supplementation which respectively enhances digestive absorption of phosphate and compensates renal phosphate wasting. This treatment can be effective in treating rickets and osteomalacia and their associated symptoms, as well as improve dental mineralization; however, it does not correct renal phosphate wasting. Potential complications include hyperparathyroidism and/or nephrocalcinosis. In adults, the benefit of continuing conventional treatment remains debated. Burosumab, an anti-FGF23 humanized antibody approved in Europe and the USA, is an alternative treatment to the conventional treatment that lowers circulating FGF-23 levels and thus corrects renal phosphate wasting, rickets and osteomalacia. Management also includes regular dental and orthodontic care in all patients, neurosurgery in certain cases, possible orthopedic interventions, hearing aids, physiotherapy and nutritional follow-up.
Prognosis
With optimal treatment and multidisciplinary care initiated early in life, prognosis can be good. Skeletal deformities can be avoided or corrected by medical treatment and if necessary corrective orthopedic surgery (preferably at the end of growth). Final height remains compromised. In adults who did not receive optimal care, chronic musculoskeletal symptoms lead to physical disabilities and impaired quality of life.

                            Last update:
                            August 2022

                            - Expert reviewer(s):
                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*

                                * European Reference Network


X-linked immunoneurologic disorder is characterized by immune deficiency and neurological disorders in females, and by neonatal death in males.

Summary:
Epidemiology
The syndrome has been described in only one family with nine affected individuals (five males and four females) spanning two generations.
Clinical description
Symptomatic females present slowly progressive proximal muscle weakness, leg hyperreflexia, pes cavus, increased muscle tone in the legs, poor bladder function, static reduced night vision, and frequent sinopulmonary infections associated with IgG2 deficiency. Males present with low birth weight and severe hypotonia that leads to death in the neonatal period.
Etiology
The gene locus has been mapped to Xq26-qter.
Differential diagnosis
The syndrome should be considered in the differential diagnosis of hereditary spastic paraplegia in females and of other causes of severe neonatal hypotonia in males.
Genetic counseling
The condition is thought to be transmitted in an X-linked dominant manner.

                            Last update:
                            August 2009


X-linked intellectual disability due to GRIA3 mutations

A rare, genetic, X-linked syndromic intellectual disability disorder characterized by moderate to severe intellectual disability associated with epilepsy, short stature, autistic features and behavioral problems, such as self injury and aggressive outbursts. Observed facial dysmorphism includes brachycephaly, prominent supraorbital ridges, and deep set eyes. Additional variable manifestations include malposition of feet, asthenic habitus, hyporeflexia, bowel occlusions, hydronephrosis, ren arcuatus, delayed motor development and disturbed sleep-wake cycle.


X-linked intellectual disability, Abidi type is characterized by X-linked intellectual deficit and mild variable manifestations, including short stature, small head circumference, sloping forehead, hearing loss, abnormally shaped ears, and small testes. It has been described in eight affected males from three generations.


X-linked intellectual disability, Armfield type is characterised by intellectual deficiency, short stature, seizures, and small hands and feet. It has been described in six males from three generations of one family. Three of them also had cataracts/glaucoma and two of them had cleft palate. The locus has been mapped to the terminal 8 Mb of Xq28.


X-linked intellectual disability, Cabezas type

An X-linked syndromic intellectual disability characterized by developmental delay, intellectual disability (ID) with severe speech impairment, and short stature. Variable additional clinical features have been associated, including behavioral disturbances, gait abnormalities, tremor, seizures, hypogonadism, truncal obesity, unspecific facial dysmorphism, and small hands and feet.

Summary:
Epidemiology
The prevalence of Cabezas syndrome (CS) is unknown. It is estimated that CS accounts for 3% of X-linked intellectual disability. To date, around 120 cases have been reported in the literature. Males are predominantly affected.
Clinical description
CS typically presents in childhood and the penetrance of CS is age-dependent, with less specific clinical features in early childhood which progress over time. It is characterized by mild to severe intellectual disability with disproportionate, severe speech impairment. Other neurologic problems include behavioural disturbances (mainly hyperactivity and aggressive behaviour), gait abnormalities, tremors, seizures (more common in young children), and variable and unspecific cerebral abnormalities (such as malformations of cortical development, including polymicrogyria, ventriculomegaly, and decreased white matter volume). Most of the described patients also have short stature, truncal obesity, hypogonadism, and small hands and feet. The facial phenotype is unspecific and evolves with age. The most frequent facial dysmorphisms are prominent lower lip and low-set ears. Additional features include urogenital anomalies (such as undescended and/or small testes, hypospadias, and small penis), gynecomastia, kyphosis, pes cavus and sandal gap. Females are mainly asymptomatic but in rare cases can present learning disability, attention deficit disorder, or tremor.
Etiology
This syndrome is caused by pathogenic variants in CUL4B gene (Xq24), encoding a scaffold protein of the cullin 4B-RING ubiquitin ligase (E3) complex, which is crucial in the regulation of the degradation of cellular proteins.
Diagnostic methods
Molecular genetic testing approaches can include a combination of chromosomal microarray and Next Generation Sequencing-based multigene panel or a comprehensive genomic testing (whole-exome sequencing or genome sequencing).
Differential diagnosis
Differential diagnosis includes Börjeson-Forssman-Lehmann syndrome, Wilson-Turner syndrome and Smith-Fineman-Myers syndrome.
Antenatal diagnosis
Prenatal diagnosis can be offered if the disease-causing mutation has been identified in a family member.
Genetic counseling
Genetic counselling should be proposed to parents of affected individuals. It is inherited in an X-linked manner. If the mother is a carrier of the pathogenic variant, the chance of transmitting the pathogenic variant at each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Female carriers are usually asymptomatic but in rare cases can exhibit a mild phenotype.
Management and treatment
Management is symptomatic and should be multidisciplinary, usually addressing developmental delay. It can include physical, occupational and speech therapy, including nonverbal methods of communication. In patients with seizures, anticonvulsant medication is needed. Medication may also be required in patients with behavioural disturbances and/or hypogonadism.
Prognosis
Longitudinal data are insufficient to determine life expectancy. However, it is not a life-threatening condition and survival into adulthood is expected. Autonomy is limited and depends on the severity of intellectual disability.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Marcia RODRIGUES | ITHACA* - Dr Marta P. SOARES | ITHACA*

                                * European Reference Network


X-linked intellectual disability, Cantagrel type

A rare X-linked intellectual disability characterized by marked neonatal hypotonia, progressive quadriparesia, severely delayed developmental milestones (walking at 3 years of age), gastroesophageal reflux, stereotypic movements of the hands, esotropia and infantile autism.


X-linked intellectual disability, Cilliers type

A rare developmental defect characterized by mild intellectual deficit associated with short stature, hypergonadotropic hypogonadism, microcephaly and mild facial dysmorphism (deep-set eyes, prominent supraorbital ridges, a high nasal bridge and large ears).

Summary:
Epidemiology
It has been described in four males from one family.
Etiology
The syndrome is mapped to the Xq25-q26 region of the X-chromosome.
Genetic counseling
The syndrome was transmitted in an X-linked recessive manner.

                            Last update:
                            May 2009


X-linked intellectual disability, Golabi-Ito-Hall type

An X-linked intellectual disability syndrome (XLMR) characterized by intellectual deficiency, microcephaly and short stature. It belongs to the group of disorders collectively referred to as Renpenning syndrome.

Summary:
Epidemiology
It has been reported in only one family, with three affected patients.
Clinical description
Moderate to severe intellectual deficiency (IQ<50) is seen in all cases as are marked facial characteristics (long narrow face with upslanting palpebral fissures). Spastic diplegia is common. Golabi-Ito-Hall syndrome shows atrial septal defects and severe growth restriction (head circumference and length) but unlike other syndromes in the Renpenning group, small testes are not observed.
Etiology
It is caused by a missense mutation in the PQBP1 gene on exon 3 that leads to deregulated splicing that alters an amino acid in the gene's WW domain.
Genetic counseling
Golabi-Ito-Hall syndrome follows an X-linked recessive pattern of inheritance. Genetic testing is possible to identify carrier females and to inform them of the risk of passing on the gene to their offspring.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                            Pr Vincent DES PORTES


X-linked intellectual disability, Hedera type is a rare X-linked intellectual disability syndrome characterized by an onset in infancy of delayed motor and speech milestones, generalized tonic-clonic seizures and drop attacks, and mild to moderate intellectual disability. Additional, less common manifestations include scoliosis, ataxia (resulting in progressive gait disturbance), and bilateral pes planovalgus. Physical appearance is normal with no dysmorphic features reported.


X-linked intellectual disability, Miles-Carpenter type

X-linked mental retardation, Miles-Carpenter type is characterised by severe intellectual deficit, microcephaly, exotropia and low digital arches.

Summary:
Epidemiology
It has been described in four male members of one family.
Clinical description
Joint hypermobility, distal muscle wasting, hypogonadism and rocker bottom feet were also reported. Low digital arches and exotropia were described in several female members of the family.
Genetic counseling
Transmission is X-linked and the causative gene has been mapped to Xq13-q22.

                            Last update:
                            March 2008


X-linked intellectual disability, Najm type

Najm type X-linked intellectual deficit is a rare cerebellar dysgenesis syndrome characterized by variable clinical manifestations ranging from mild intellectual deficit with or without congenital nystagmus, to severe cognitive impairment associated with cerebellar and pontine hypoplasia/atrophy and abnormalities of cortical development.

Summary:
Epidemiology
Prevalence of this rare neurological syndrome is unknown. Up to 35 families have been reported to date.
Clinical description
Patients (mostly females) have been reported to have variable clinical manifestations including intellectual deficit, severe developmental delay, seizures, unsteady gait, sensorineural hearing loss and postnatal microcephaly (in most cases). Minor facial anomalies include: low or broad forehead, hypertelorism, long philtrum and micrognathia. Ocular findings are also variable and include congenital nystagmus, strabismus, cataracts, myopia or reduced visual acuity. Males appear to be more severely affected.
Etiology
Point mutations and deletions in the CASK gene (Xp11.4) have been found in patients with this syndrome.
Diagnostic methods
Magnetic resonance imaging (MRI) generally shows pontocerebellar hypoplasia/atrophy and simplified cortical gyri. Molecular genetic testing is needed to confirm diagnosis.
Genetic counseling
Transmission follows an X-linked dominant pattern.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Ginevra ZANNI


X-linked intellectual disability, Nascimento type is a rare X-linked intellectual disability syndrome characterized by intellectual disability (with severe speech impairment), a myxedematous appearance, dysmorphic facial features (including large head, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide mouth with everted lower lip and downturned lip corners), low posterior hairline, short, broad neck, marked general hirsutism and abnormal hair whorls, skin changes (e.g. dry skin or hypopigmented spots), widely spaced nipples, obesity, micropenis, onychodystrophy and seizures.


X-linked intellectual disability, Pai type

A rare X-linked syndromic intellectual disability characterized by global developmental delay and severe intellectual disability, seizures, and recurrent lower respiratory tract infections, resulting in premature death in affected males. Additional reported manifestations include mild dysmorphic facial features (such as epicanthic folds, high nasal bridge, or small mouth), gait disturbances, brisk tendon reflexes, delayed bone age, and tapering fingers. No evident heterozygous manifestation has been reported in females.


X-linked intellectual disability, Schimke type

A rare X-linked syndromic intellectual disability characterized by intellectual deficit, growth retardation with short stature, deafness and ophthalmoplegia. Choreoathetosis with muscle spasticity generally appears during childhood.


X-linked intellectual disability, Seemanova type is characterised by microcephaly, intellectual deficit, growth retardation and hypogenitalism. It has been described in four boys from one family. A characteristic facies and ophthalmologic anomalies were also present and included microphthalmia, microcornea and cataract. Transmission is X-linked.


X-linked intellectual disability, Shashi type is characterised by moderate intellectual deficit, obesity, macroorchidism and a characteristic facies (large ears, a prominent lower lip and puffy eyelids). It has been described in nine boys from two families. Transmission is X-linked and the causative gene has been localised to the q21.3-q27 region of the X chromosome.


X-linked intellectual disability, Shrimpton type

An X-linked syndromic intellectual disability characterised by severe intellectual disability, microcephaly and short stature in male patients. Strabismus and spastic diplegia have also been described.


X-linked intellectual disability, Siderius type is characterised by mild to borderline intellectual deficit associated with cleft lip/palate. Preaxial polydactyly, large hands and cryptorchidism are sometimes present. The syndrome has been described in seven boys from two families. Transmission is X-linked and the syndrome is caused by mutations in the PHF8 gene, localised to the p11.21 region of the X chromosome.


X-linked intellectual disability, Snyder type is a rare X-linked intellectual disability syndrome characterized by hypotonia, asthenic build with diminished muscle mass, severe generalized psychomotor delay, unsteady gait and moderate to severe intellectual disability, as well as a long, thin, asymmetrical face with prominent lower lip, long fingers and toes and nasal, dysarthric or absent speech. Bone abnormalities (e.g., osteoporosis, kyphoscoliosis, fractures, joint contractures) are also characteristic. Myoclonic, or myoclonic-like, seizures and renal abnormalities have been associated in some patients.


X-linked intellectual disability, Stevenson type is characterised by intellectual deficit, hypotonia, absent deep tendon reflexes, tapered fingers and excessive fingerprint arches, genu valgum, a characteristic face and small teeth. It has been described in four males from two generations of one family. The causative gene appears to be located in the q13 region of the X chromosome.


X-linked intellectual disability, Stocco Dos Santos type is characterised by severe intellectual deficit with hyperactivity, language delay, congenital hip luxation, short stature, kyphosis and recurrent respiratory infections. Aggressive behaviour and frequent epileptic seizures may also be present. The syndrome has been described in four boys from the same family. Transmission is X-linked and is caused by mutations in the KIAA1202 gene, localised to the Xp11.2 region.


X-linked intellectual disability, Stoll type is characterised by intellectual deficit, short stature and characteristic facies (hypertelorism, prominent forehead, frontal bossing, a broad nasal tip and anteverted nares). It has been described in four males from three generations of the same family. Two females from this family also displayed intellectual deficit and the characteristic facies. Transmission is X-linked.


X-linked intellectual disability, Van Esch type

A rare, genetic, syndromic intellectual disability characterized by developmental delay, mild to moderate intellectual disability, low birth weight, moderate to severe short stature, microcephaly and variable hypergonadotropic hypogonadism. Mild facial dismorfism include upslanted palpebral fissures and prominent nasal bridge.


X-linked intellectual disability, Wilson type is characterised by severe intellectual deficit with mutism, epilepsy, growth retardation and recurrent infections. It has been described in three males from three generations of one family. The causative gene has been localised to the 11p region of the X chromosome.


X-linked intellectual disability-acromegaly-hyperactivity syndrome is characterised by severe intellectual deficit, acromegaly and hyperactivity. The syndrome has been described in two half-brothers. Dysarthria, aggressive behaviour, a characteristic facies (an acromegalic and triangular face with a long nose) and macroorchidism were also present. The mother displayed moderate intellectual deficit and milder facial anomalies. Central nervous system anomalies were identified in the two boys: subarachnoid cysts and hyperdensity in the pontine region.


X-linked intellectual disability-ataxia-apraxia syndrome

A rare, X-linked syndromic intellectual disability disorder characterized by non-progressive ataxia, apraxia, variable intellectual disability and/or visuospatial, visuographic and visuoconstructive dysfunctions in male patients. Seizures, congenital clubfoot and macroorchidism have also been associated. Partial clinical expression was noted in obligate female carriers. There have been no further descriptions in the literature since 1992.


X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome is a rare X-linked syndromic intellectual disability disorder characterized by profound intellectual disability, global developmental delay with absent speech, seizures, large joint contractures, abnormal position of thumbs and middle-age onset of cardiomegaly and atrioventricular valve abnormalities, resulting in subsequent congestive heart failure. Additional features include variable facial dysmorphism (notably large ears with overfolded helix) and large testes.


X-linked intellectual disability-cerebellar hypoplasia syndrome

X-linked intellectual deficit-cerebellar hypoplasia, also known as OPHN1 syndrome, is a rare syndromic form of cerebellar dysgenesis characterized by moderate to severe intellectual deficit and cerebellar abnormalities.

Summary:
Epidemiology
OPHN1 syndrome is very rare. To date, up to 12 families have been reported.
Clinical description
Affected male patients present moderate to severe intellectual disability, hypotonia, severe developmental delay, early-onset complex partial or tonic-clonic seizures, strabismus, dysmetria and occasionally ataxia. Cryptorchidism and genital hypoplasia have been reported. Some patients have abnormal behavior and a characteristic facial phenotype (long face, prominent forehead, infraorbital creases, deep-set eyes, upturned philtrum and large ears). Carrier females have been reported to have mild learning disabilities, mild cognitive impairment, strabismus, and subtle facial changes.
Etiology
Various mutations including deletions and splice site mutations in the OPHN1 gene (Xq12) have been reported in patients with this syndrome.
Diagnostic methods
Neuroradiological findings include posterior vermis dysgenesis, vermian parasagittal cleft, cerebellar hypoplasia, cortical atrophy, and enlargement of the cerebral ventricles. Molecular genetic testing is needed to confirm diagnosis.
Genetic counseling
Transmission appears to follow an X-linked semi-dominant pattern.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Ginevra ZANNI


X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, growth retardation, hypotonia, cerebellar symptoms such as ataxia, spondyloepiphyseal dysplasia, and dysmorphic craniofacial features (including microcephaly, dolichocephaly, prominent ears, epicanthus, broad nasal bridge, long and flat philtrum, or small mouth). Additional reported manifestations are epilepsy, retinitis pigmentosa, and urogenital abnormalities, among others. Brain imaging may show cerebellar hypoplasia.


X-linked intellectual disability-craniofacioskeletal syndrome is a rare, hereditary, syndromic intellectual disability characterized by craniofacial and skeletal abnormalities in association with mild intellectual disability in females and early postnatal lethality in males. In addition to mild cognitive impairment, females present with microcephaly, short stature, skeletal features and extra temporal lobe gyrus. In males, intrauterine growth impairment, cardiac and urogenital anomalies have been reported.


X-linked intellectual disability-cubitus valgus-dysmorphism syndrome is characterised by moderate intellectual deficit, marked cubitus valgus, mild microcephaly, a short philtrum, deep-set eyes, downslanting palpebral fissures and multiple nevi. Less than ten individuals have been described so far. Transmission is thought to be X-linked recessive.


X-linked intellectual disability-Dandy-Walker malformation-basal ganglia disease-seizures syndrome

A rare central nervous system malformation characterized by severe intellectual deficit, early hypotonia with progression to spasticity and contractures, choreoathetosis, seizures, dysmorphic face (long face with prominent forehead), and brain imaging abnormalities such as Dandy-Walker malformation, and iron deposition.


X-linked intellectual disability-dysmorphism-cerebral atrophy syndrome

An X-linked syndromic intellectual disability characterized by intellectual disability, subcortical cerebral atrophy, dental anomalies, patella luxation, lower back skin dimple, and dysmorphic facial features.


X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome is characterised by intellectual deficit, epilepsy, facial dysmorphism and progressive joint contractures. It has been described in two boys. Hypotonia and feeding problems at birth were also reported. The mode of transmission is X-linked.


X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, growth retardation, hearing impairment, characteristic facial dysmorphology (including prominent supraorbital ridges, downslanting palpebral fissures, deep-set eyes, long face, sagging cheeks, anteverted nares, and pointed chin), generalized hypotonia, joint hypermobility, gluteal crease with sacral caudal remnant and sacral dimple, and variable neurological features. Various ophthalmic, cutaneous, musculoskeletal, gastrointestinal, and cardiovascular anomalies have also been described.

Summary:
Epidemiology
Due to the small number of known affected individuals, the prevalence of this condition remains unknown. Globally, some 30 cases are known.
Clinical description
The main clinical features include growth retardation, delayed speech and language development, delayed gross motor development, generalized hypotonia, intellectual disability and symptoms of autism spectrum disorder. Microcephaly, facial dysmorphism, hearing impairment, variable brain morphological abnormalities, and congenital heart defects, hypospadias and cryptorchidism have also been reported.
Etiology
The disorder is caused by pathogenic mutations in the TAF1 gene (Xq13.1). The encoded protein, transcription initiation factor TFIID subunit 1, is a part of the transcription factor II D complex that participates in the initiation of the transcription of RNA polymerase II transcription-dependent genes.
Diagnostic methods
Diagnosis is based on clinical examination and genetic testing.
Differential diagnosis
The main differential diagnosis options include other X-linked intellectual disability syndromes that involve similar symptoms or clinical findings.
Antenatal diagnosis
Antenatal diagnosis is possible if a familial pathogenic variant has been identified.
Genetic counseling
The pattern of inheritance is X-linked. Where the female is a carrier, at risk couples should be informed that for each pregnancy the male offspring have a 50% risk of being affected and female offspring have a 50% risk of being a carrier. Females may rarely be affected due to skewed X chromosome inactivation.
Management and treatment
Management is symptomatic. After initial diagnosis, evaluation by a pediatric urologist, pediatric cardiologist, pediatric neurologist, otorhinolaryngologist or other relevant specialist may be warranted to rule out associated congenital abnormalities.
Prognosis
Studies suggest that the symptoms are generally not progressive; however, individual cases with progressive symptomatology have been reported. Longitudinal data regarding life expectancy is currently unavailable due to the small number of known cases.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Dr Outi KUISMIN | ITHACA* - Dr Leila SOIKKONEN | ITHACA*

                                * European Reference Network


X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by moderate intellectual disability, dysmorphic facial features (such as prominent glabella, synophrys, and prognathism), generalized hirsutism, bilateral single palmar creases, and seizures. Additional reported manifestations include slowly progressive neurological deterioration with muscular weakness and impaired gait and balance, as well as hypogammaglobulinemia with specific absence of plasma and/or secretory IgA, among others. Brain imaging may show mild cerebellar atrophy and thin corpus callosum.


X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome is a rare X-linked intellectual disability syndrome characterized by intellectual disability associated with short stature, obesity, primary hypogonadism and an ichthyosiform skin condition. There have been no further descriptions in the literature since 1982.


X-linked intellectual disability-hypotonia-facial dysmorphism-aggressive behavior syndrome

A rare X-linked syndromic intellectual disability characterized by severe to profound intellectual disability, muscular hypotonia in childhood, delayed walking, delayed or minimal/absent speech, behavioral abnormalities including aggressiveness, agitation, and self-injurious behavior, and dysmorphic facial features (such as triangular face with high forehead, prominent ears, and small, pointed chin). Additional reported manifestations include microcephaly, short stature, and seizures, among others.


X-linked intellectual disability-hypotonia-movement disorder syndrome

A rare, genetic, syndromic intellectual disability characterized by mild to severe intellectual disability associated with variable features, including hypotonia, dyskinesia, spasticity, wide-based gait, microcephaly, epilepsy and behavioral problems. MRI imaging may show a corpus callosum hypoplasia or ventricular enlargement. Other variable features, such as joint hyperlaxity, skin pigmentary abnormalities, and visual impairment, have also been reported.


X-linked intellectual disability-limb spasticity-retinal dystrophy-arginine vasopressin deficiency

X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome is a rare genetic neurometabolic disease characterized by severe intellectual disability, spastic quadraparesis, Leber´s congenital amaurosis and diabetes insipidus. Additional manifestations include facial dysmorphy (dolichocephalic skull, hypertelorism, deep-set eyes, hypoplastic nares, low-set ears), short stature, truncal hypotonia and axial hypertonia. Brain anomalies (e.g. thin corpus callosum with lack of isthmus and tapered splenium, hypoplasia or atrophy of the optic chiasm, prominent lateral ventricles, diminished white matter), described on magnetic resonance imaging, have been reported. High prenatal α-fetoprotein and intrauterine growth restriction is observed in routine pregnancy examination.


X-linked intellectual disability-macrocephaly-macroorchidism syndrome

An X-linked syndromic intellectual disability characterized by intellectual disability, macrocephaly, macroorchidism, prominent eyebrows and jaws and abnormal ears. Males are predominantly affected, some females show lower cognitive abilities.


X-linked intellectual disability-plagiocephaly syndrome

A rare, syndromic intellectual disability characterized by severe intellectual deficit, brachycephaly, plagiocephaly, and prominent forehead in male patients. Females may display moderate intellectual deficit without craniofacial dysmorphism. There have been no further descriptions in the literature since 1992.


X-linked intellectual disability-psychosis-macroorchidism syndrome

An X-linked syndromic intellectual disability characterized by developmental delay, variable degree of intellectual disability, speech delay or absent speech, pyramidal signs, tremor, macroorchidism and variable mood and behavior problems, including psychosis and autistic-like behavior. Males are predominantly affected, some females show lower cognitive abilities.


X-linked intellectual disability-retinitis pigmentosa syndrome is characterized by moderate intellectual deficit and severe, early-onset retinitis pigmentosa. It has been described in five males spanning three generations of one family. Some patients also had microcephaly. It is transmitted as an X-linked recessive trait.


X-linked intellectual disability-seizures-psoriasis syndrome

A rare, X-linked syndromic intellectual disability disorder characterized by severe intellectual disability, psychomotor developmental delay, generalized seizures, and psoriasis. Mild craniofacial dysmorphism, such as hypertelorism, broad nasal bridge, anteverted nares, macrostomia, highly arched palate and large ears, is also associated. There have been no further descriptions in the literature since 1988.


X-linked intellectual disability-short stature-overweight syndrome is a multiple congenital anomalies syndrome characterized by borderline to severe intellectual disability, speech delay, short stature, elevated body mass index, a pattern of truncal obesity (reported in older males), and variable neurologic features (e.g. hypotonia, tremors, gait disturbances, behavioral problems, and seizure disorders). Less common manifestations include microcephaly, microorchidism and/or microphallus. Dysmorphic features have been reported in some patients but no consitent pattern has been noted.


X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome

A rare genetic disease characterized by congenital contractures of the distal interphalangeal joints, progressive stiffness of the shoulders and neck, keloid scarring, increased optic cup-to-disc ratio, and renal stones. Additional reported features include arthritis, osteoporosis, hypoplastic flexion creases, clinodactyly, anxiety, and facial dysmorphism (such as sloping forehead, prominent supraorbital ridges, downslanting palpebral fissures, prominent ears, and high arched palate). Female carriers exhibit a variable, milder phenotype.


X-linked lethal multiple pterygium syndrome is a rare, genetic, developmental defect during embryogenesis characterized by the typical lethal multiple pterygium syndrome presentation (comprising of multiple pterygia, severe arthrogryposis, cleft palate, cystic hygromata and/or fetal hydrops, skeletal abnormalities and fetal death in the 2nd or 3rd trimester) with an X-linked pattern of inheritance.


X-linked lissencephaly with abnormal genitalia

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by lissencephaly, agenesis of the corpus callosum and other cerebral structural anomalies, early-onset intractable seizures, and ambiguous genitalia. Consequences of hypothalamic dysfunction, such as disturbed temperature regulation, may be observed. Additional anomalies including dysmorphic craniofacial features have been reported. The disease is fatal in infancy or childhood in males, while female carriers may be unaffected or show a milder phenotype with developmental delay, behavioral abnormalities, and seizures.


X-linked lymphoproliferative disease due to SAP deficiency

A rare, genetic, primary immunodeficiency disorder characterized by an abnormal immune response to Epstein-Barr virus (EBV) infection, caused by hemizygous mutations in the X-linked SH2D1A gene, resulting in B cell lymphoproliferation and manifesting with various phenotypes which include EBV-driven severe or fulminant mononucleosis, hemophagocytic lymphohistiocytosis (presenting with fulminant hepatitis, hepatic necrosis, bone marrow hypoplasia, and neurological involvement), hypogammaglobulinemia, and B-cell lymphoma. Additional variable manifestations include vasculitis, lymphomatoid granulomatosis, aplastic anemia, and chronic gastritis. Occasionally, T-cell lymphoma may be observed. Laboratory findings include normal or increased activated T cells and reduced memory B cells.


X-linked lymphoproliferative disease due to XIAP deficiency

A rare, genetic, primary immunodeficiency disorder characterized by an abnormal immune response to Epstein-Barr virus (EBV) infection, caused by hemizygous mutations in the X-linked XIAP gene, resulting in B cell lymphoproliferation and manifestating with various phenotypes which include EBV-driven hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, recurrent splenomegaly, hepatitis, colitis, and intestinal bowel disease with features of Crohn's disease. Additional manifestations include variable auto-inflammatory symptoms such as uveitis, arthritis, skin abscesses, erythema nodosum, and nephritis. Neurological involvement is rare and lymphoma is never observed. Laboratory findings include normal or increased activated T cells, low or normal iNKT cells, and normal or reduced memory B cells.


X-linked mandibulofacial dysostosis is an extremely rare multiple congenital abnormality syndrome that is characterized by microcephaly, malar hypoplasia with downslanting palpebral fissures, highly arched palate, apparently low-set and protruding ears, micrognathia, short stature, bilateral hearing loss, and learning disability. Occasionally, additional features have been observed such as bilateral cryptorchidism, cardiac valvular lesions, body asymmetry, and pectus excavatum.